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WO2024081889A1 - 4h-pyrido[1,2-a]pyrimidin-4-one derivatives for treating cancer - Google Patents

4h-pyrido[1,2-a]pyrimidin-4-one derivatives for treating cancer Download PDF

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Publication number
WO2024081889A1
WO2024081889A1 PCT/US2023/076857 US2023076857W WO2024081889A1 WO 2024081889 A1 WO2024081889 A1 WO 2024081889A1 US 2023076857 W US2023076857 W US 2023076857W WO 2024081889 A1 WO2024081889 A1 WO 2024081889A1
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Prior art keywords
compound
optionally substituted
alkyl
independently selected
pyrimidin
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PCT/US2023/076857
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French (fr)
Inventor
Brett Busch
Nicholas Simon Stock
Advait Nagle
Evan Nathaniel Feinberg
Martin INDARTE
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GENESIS THERAPEUTICS Inc
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GENESIS THERAPEUTICS Inc
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Priority to EP23801274.4A priority Critical patent/EP4602043A1/en
Publication of WO2024081889A1 publication Critical patent/WO2024081889A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • PI3K phosphatidylinositol 4,5-bisphosphate 3-kinase
  • PI3K ⁇ phosphatidylinositol 4,5-bisphosphate 3-kinase
  • PI3K Phosphatidylinositol 4,5-bisphosphate 3-kinase
  • PI3K ⁇ Phosphatidylinositol 4,5-bisphosphate 3-kinase
  • PI3K inhibitors have been problematic for several reasons, in particular, inability to specifically inhibit signaling by mutant PI3K ⁇ while sparing wild-type PI3K ⁇ , and the related dose-limiting toxicities that prevent sustained PI3K pathway suppression.
  • alpelisib is a PI3K inhibitor that is equipotent against wild-type and mutant forms of PI3K ⁇ , which results in dose-limiting toxicities and hyperglycemia.
  • selectively targeting PI3K ⁇ represents an approach for the treatment of proliferative disorders such as cancer.
  • R 1 is hydrogen, cyano, C3-C6 cycloalkyl, C1-C6 alkyl optionally substituted with phenyl optionally substituted with halogen, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 alkoxyalkyl;
  • R 1 is hydrogen, cyano, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted with phenyl optionally substituted with halogen
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • a method for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
  • a method of treating a PI3K ⁇ -associated disease in a subject comprising administering to a subject identified or diagnosed as having a PI3K ⁇ -associated disease a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
  • This disclosure also provides a method of treating a PI3K ⁇ -associated disease in a subject, comprising: determining that the cancer in the subject is a PI3K ⁇ -associated disease; and administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Further provided herein is a method of treating a PI3K ⁇ -associated cancer in a subject, comprising administering to a subject identified or diagnosed as having a PI3K ⁇ -associated cancer a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
  • This disclosure also provides a method of treating a PI3K ⁇ -associated cancer in a subject, comprising: determining that the cancer in the subject is a PI3K ⁇ -associated cancer; and administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
  • a method of treating a subject comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein, to a subject having a clinical record that indicates that the subject has a dysregulation of a PIK3CA gene, a PI3K ⁇ protein, or expression or activity or level of any of the same.
  • This disclosure also provides a method for inhibiting PI3K ⁇ in a mammalian cell, comprising contacting the mammalian cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • Other embodiments include those described in the Detailed Description and/or in the claims. Additional Definitions To facilitate understanding of the disclosure set forth herein, a number of additional terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well- known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
  • terapéuticaally effective amount means an amount of compound that, when administered to a subject in need of such treatment, is sufficient to (i) treat a PI3K ⁇ protein- associated disease, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, or (iii) delay the onset of one or more symptoms of the particular disease described herein.
  • pharmaceutically acceptable salt refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
  • the term “subject” refer to any animal, including mammals such as primates (e.g., humans), mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and/or exhibited at least one symptom of the disease to be treated and/or prevented. As used herein, terms “treat” or “treatment” refer to therapeutic or palliative measures.
  • Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • halogen refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).
  • hydroxyl refers to an -OH radical.
  • cyano refers to a -CN radical.
  • alkyl refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C 1-10 indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it.
  • Non-limiting examples include methyl, ethyl, iso-propyl, tert-butyl, n-hexyl.
  • saturated as used in this context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and/or other substituents as defined herein.
  • haloalkyl refers to an alkyl, in which one or more hydrogen atoms is/are replaced with an independently selected halogen.
  • alkoxy refers to an -O-alkyl radical (e.g., -OCH 3 ).
  • alkoxyalkyl refers to an –alkyl-O-alkyl radical (e.g., -CH 2 CH 2 OCH 3 ).
  • thioalkyl refers to an -S-alkyl radical (e.g., -SCH 3 ) or an –alkyl-S-alkyl radical (e.g., -CH 2 CH 2 SCH 3 ).
  • hydroxyalkyl refers to an alkyl, in which one or more hydrogen atoms is/are replaced with hydroxyl.
  • aryl refers to a 6-20 membered all carbon ring system wherein at least one ring in the system is aromatic (e.g., 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system). Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.
  • cycloalkyl refers to cyclic saturated hydrocarbon groups having, e.g., 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons.
  • cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Cycloalkyl may include multiple fused and/or bridged rings.
  • Non-limiting examples of fused/bridged cycloalkyl includes: bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, and the like.
  • Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom).
  • spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like.
  • heteroaryl refers to a ring system having 5 to 20 ring atoms, such as 5, 6, 9, 10, or 14 ring atoms; wherein at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, S, Si, and B, and at least one ring in the system is aromatic (but does not have to be a ring which contains a heteroatom, e.g. tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl).
  • Heteroaryl groups can include monocyclic, bridged, fused, and spiro ring systems, so long as one ring in the system is aromatic.
  • heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl,
  • the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.
  • pyridone e.g., pyrimidone (e.g., pyridazinone (e.g., pyrazinone (e.g., and imidazolone (e.g., wherein
  • heterocyclyl refers to a saturated or partially unsaturated ring systems with 3- 16 ring atoms (e.g., 3-8 membered monocyclic, 5-12 membered bicyclic, or 10-14 membered tricyclic ring system) having at least one heteroatom selected from O, N, S, Si, and B, wherein one or more ring atoms may be substituted by 1-3 oxo (forming, e.g., a lactam) and one or more N or S atoms may be substituted by 1-2 oxido (forming, e.g., an N-oxide, an S-oxide, or an S,S- dioxide), valence permitting.
  • Heterocyclyl groups include monocyclic, bridged, fused, and spiro ring systems.
  • heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl, and the like.
  • Heterocyclyl may include multiple fused and bridged rings.
  • Non-limiting examples of fused/bridged heteorocyclyl includes: 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane, 3- azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6- azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, azabicyclo[3.2.1]octane, 2-oxabicyclo[1.1.0]butane, 2-oxabicyclo[2.1.0]pentane, 2- oxabicyclo[1.1.1]p
  • Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom).
  • spirocyclic heterocyclyls include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1- azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6- azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane 2,5- diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2-oxaspiro[2.2]pentane, 4-oxaspiro[2.5]octane, 1-oxaspiro[3.5]nonane, 2-
  • an “aralkyl” refers to an aryl group, as defined herein, connected to the remainder of the molecule via a divalent C1-C6 alkyl group, as described herein.
  • Non-limiting examples of an aralkyl group are benzyl, ethylphenyl, methylnaphthyl, and the like.
  • a “heteroaralkyl” refers to a heteroaryl group, as defined herein, connected to the remainder of the molecule via a divalent C1-C6 alkyl group, as described herein.
  • Non-limiting examples of an aralkyl group are methylpyridyl, ethylpyrimidinyl, methylimidazolyl, and the like.
  • aromatic rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like.
  • a ring when a ring is described as being “partially unsaturated”, it means said ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or tirple bonds between constituent ring atoms), provided that the ring is not aromatic.
  • rings examples include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.
  • rings and cyclic groups e.g., aryl, heteroaryl, heterocyclyl, cycloalkyl, and the like described herein
  • rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms (e.g., [x.x.0] ring systems, in which 0 represents a zero atom bridge (e.g., )); (ii) a single ring atom (spiro-fused ring systems) (e.g., or (iii) a contiguous array of ring atoms (bridged ring systems having all bridge lengths > 0) (e.g.,
  • atoms making up the compounds of the present embodiments are intended to include
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium
  • isotopes of carbon include 13 C and 14 C.
  • the compounds generically or specifically disclosed herein are intended to include all tautomeric forms.
  • a compound containing the moiety: encompasses the tautomeric form containing the moiety: .
  • a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms.
  • the compounds provided herein may encompass various stereochemical forms.
  • the compounds also encompass enantiomers (e.g., R and S isomers), diastereomers, as well as mixtures of enantiomers (e.g., R and S isomers) including racemic mixtures and mixtures of diastereomers, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds.
  • enantiomers e.g., R and S isomers
  • diastereomers e.g., R and S isomers
  • mixtures of enantiomers e.g., R and S isomers
  • Formulae (I) Compounds Some embodiments provide a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: R 1 is hydrogen, cyano, C3-C6 cycloalkyl, C1-C6 alkyl optionally substituted with phenyl optionally substituted with halogen, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 alkoxyalkyl; R 2 is phenyl optionally substituted with 1-4 independently selected R 2A , 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R 2A , 4-10 membered heterocyclyl optionally substituted with 1-4 independently selected R 2A , 4-10 membered cycloalkyl optionally substituted
  • R 1 is hydrogen, cyano, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted with phenyl optionally substituted with halogen
  • R 1 is hydrogen. In some embodiments, R 1 is cyano. In some embodiments, R 1 is C3-C6 cycloalkyl. In some embodiments, R 1 is cyclopropyl or cyclobutyl. In some embodiments, R 1 is C1-C6 alkyl optionally substituted with phenyl optionally substituted with halogen. In some embodiments, R 1 is C1-C6 alkyl substituted with phenyl optionally substituted with halogen. In some embodiments, R 1 is C1-C6 alkyl substituted with phenyl substituted with halogen. In some embodiments, R 1 is para-fluorobenzyl.
  • R 1 is C1-C6 alkyl substituted with phenyl. In some embodiments, R 1 is benzyl. In some embodiments, R 1 is ethyl-1-phenyl or ethyl-2-phenyl. In some embodiments, R 1 is C1- C6 alkyl. In some embodiments, R 1 is methyl, ethyl, or isopropyl. In some embodiments, R 1 is methyl. In some embodiments, R 1 is C1-C6 thioalkyl. In some embodiments, R 1 is C1-C3 thioalkyl. In some embodiments, R 1 is thiomethyl, thioethyl, or thiopropyl.
  • R 1 is methyl-thiomethyl, methyl-thioethyl, or ethyl-thiomethyl. In some embodiments, R 1 is thiomethyl. In some embodiments, R 1 is C1-C6 haloalkyl. In some embodiments, R 1 is C1-C3 haloalkyl. In some embodiments, R 1 is C1-C3 fluoroalkyl. In some embodiments, R 1 is CF3. In some embodiments, R 1 is CHF2. In some embodiments, R 1 is C1-C6 alkoxy. In some embodiments, R 1 is C1-C3 alkoxy.
  • R 1 is –OCH 3 , –OCH 2 CH 3 , or –OCH 2 CH 2 CH 3 . In some embodiments, R 1 is –OCH 3 . In some embodiments, R 1 is C1-C6 alkoxyalkyl. In some embodiments, R 1 is C1-C3 alkoxyalkyl. In some embodiments, R 1 is –CH 2 OCH 3 , –CH 2 OCH 2 CH 3 , or –CH 2 CH 2 OCH 3 . In some embodiments, R 1 is –CH 2 OCH 3 . In some embodiments, R 2 is phenyl optionally substituted with 1-4 independently selected R 2A .
  • R 2 is phenyl substituted with 1 or 2 independently selected R 2A . In some embodiments, R 2 is phenyl substituted with 1 R 2A . In some embodiments, R 2 is phenyl substituted with 2 independently selected R 2A . In some embodiments, R 2 is phenyl optionally substituted with 3 independently selected R 2A . In some embodiments, R 2 is phenyl. In some embodiments, R 2 is 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R 2A . In some embodiments, R 2 is 5-10 membered heteroaryl substituted with 1 or 2 independently selected R 2A . In some embodiments, R 2 is 5-10 membered heteroaryl substituted with 1 R 2A . In some embodiments, R 2 is 5-10 membered heteroaryl substituted with 1 R 2A .
  • R 2 is 5-10 membered heteroaryl substituted with 2 independently selected R 2A . In some embodiments, R 2 is 5-10 membered heteroaryl optionally substituted with 3 independently selected R 2A . In some embodiments, R 2 is 5-10 membered heteroaryl. In some embodiments, R 2 is 6 membered heteroaryl optionally substituted with 1-4 independently selected R 2A . In some embodiments, R 2 is 6 membered heteroaryl substituted with 1 or 2 independently selected R 2A . In some embodiments, R 2 is 6 membered heteroaryl substituted with 1 R 2A . In some embodiments, R 2 is 6 membered heteroaryl substituted with 2 independently selected R 2A .
  • R 2 is 6 membered heteroaryl optionally substituted with 3 independently selected R 2A . In some embodiments, R 2 is 6 membered heteroaryl. In some embodiments, R 2 is 9 membered heteroaryl optionally substituted with 1-4 independently selected R 2A . In some embodiments, R 2 is 9 membered heteroaryl substituted with 1 or 2 independently selected R 2A . In some embodiments, R 2 is 9 membered heteroaryl substituted with 1 R 2A . In some embodiments, R 2 is 9 membered heteroaryl substituted with 2 independently selected R 2A . In some embodiments, R 2 is 9 membered heteroaryl optionally substituted with 3 independently selected R 2A .
  • R 2 is 9 membered heteroaryl.
  • the heteroaryl of R 2 is pyridinyl, pyrimidinyl, pyridazinyl, indole, indazole, azaindole, azaindazole, indoline, azaindoline, isoindoline, azaisoindoline, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzoisoxazolyl, benzisothiazolyl, quinolinyl, or isoquinolinyl.
  • the heteroaryl of R 2 is pyridinyl or pyrimidinyl.
  • the heteroaryl of R 2 is indole, indazole, azaindole, azaindazole, indoline, azaindoline, isoindoline, or azaisoindoline.
  • R 2 is 4-10 membered heterocyclyl optionally substituted with 1-4 independently selected R 2A .
  • R 2 is 4-10 membered heterocyclyl substituted with 1 or 2 independently selected R 2A .
  • R 2 is 4-10 membered heterocyclyl substituted with 1 R 2A .
  • R 2 is 4-10 membered heterocyclyl substituted with 2 independently selected R 2A .
  • R 2 is 4-10 membered heterocyclyl optionally substituted with 3 independently selected R 2A . In some embodiments, R 2 is 4-10 membered heterocyclyl. In some embodiments, R 2 is 5-8 membered heterocyclyl optionally substituted with 1-4 independently selected R 2A . In some embodiments, R 2 is 5-8 membered heterocyclyl substituted with 1 or 2 independently selected R 2A . In some embodiments, R 2 is 5-8 membered heterocyclyl substituted with 1 R 2A . In some embodiments, R 2 is 5-8 membered heterocyclyl substituted with 2 independently selected R 2A .
  • R 2 is 5-8 membered heterocyclyl optionally substituted with 3 independently selected R 2A . In some embodiments, R 2 is 5-8 membered heterocyclyl. In some embodiments, the heterocyclyl of R 2 is piperidinyl, piperazinyl, or morpholinyl. In some embodiments, R 2 is 4-10 membered cycloalkyl optionally substituted with 1-4 independently selected R 2A . In some embodiments, R 2 is 4-10 membered cycloalkyl substituted with 1 or 2 independently selected R 2A . In some embodiments, R 2 is 4-10 membered cycloalkyl substituted with 1 R 2A .
  • R 2 is 4-10 membered cycloalkyl substituted with 2 independently selected R 2A . In some embodiments, R 2 is 4-10 membered cycloalkyl optionally substituted with 3 independently selected R 2A . In some embodiments, R 2 is 4-10 membered cycloalkyl. In some embodiments, R 2 is 5-7 membered cycloalkyl optionally substituted with 1-4 independently selected R 2A . In some embodiments, R 2 is 5-7 membered cycloalkyl substituted with 1 or 2 independently selected R 2A . In some embodiments, R 2 is 5-7 membered cycloalkyl substituted with 1 R 2A .
  • R 2 is C1-C3 alkoxyalkyl. In some embodiments, R 2 is –CH 2 OCH 3 , –CH 2 OCH 2 CH 3 , or – CH 2 CH 2 OCH 3 . In some embodiments, R 2 is –CH 2 OCH 3 . In some embodiments, 1, 2, 3, or 4 of R 2A are independently halogen. In some embodiments, 1, 2, or 3 of R 2A are independently fluoro or chloro. In some embodiments, 1 or 2 of R 2A are independently fluoro or chloro. In some embodiments, 1, 2, 3, or 4 of R 2A are independently cyano. In some embodiments, 1 or 2 of R 2A are cyano.
  • 1, 2, 3, or 4 of R 2A are independently C1-C6 haloalkyl. In some embodiments, 1 or 2 of R 2A are independently C1-C3 haloalkyl. In some embodiments, 1 or 2 of R 2A are trifluoromethyl. In some embodiments, 1, 2, 3, or 4 of R 2A are independently C1-C6 hydroxyalkyl. In some embodiments, 1 or 2 of R 2A are independently C1-C3 hydroxyalkyl. In some embodiments, 1, 2, 3, or 4 of R 2A are independently 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl and - NR A R B .
  • 1, 2, 3, or 4 of R 2A are independently 5-10 membered heteroaryl substituted with 1-3 substituents independently selected from C1-C6 alkyl and -NR A R B . In some embodiments, 1, 2, 3, or 4 of R 2A are independently 5-10 membered heteroaryl. In some embodiments, 1 of R 2A is 5-6 membered heteroaryl optionally substituted with 1- 3 substituents independently selected from C1-C6 alkyl and -NR A R B . In some embodiments, 1 of R 2A is 5-6 membered heteroaryl substituted with 1-3 substituents independently selected from C1-C6 alkyl and -NR A R B .
  • 1 of R 2A is 5-6 membered heteroaryl.
  • 1, 2, 3, or 4 of R 2A are independently 4-10 membered heterocyclyl.
  • 1 of R 2A is 4-10 membered heterocyclyl.
  • 1, 2, 3, or 4 of R 2A are independently C1-C6 alkyl.
  • 1, 2, or 3 of R 2A are independently C1-C3 alkyl.
  • 1, 2, or 3 of R 2A are methyl.
  • 1 or 2 of R 2A are independently C1-C6 alkyl.
  • 1 or 2 of R 2A are independently C1-C3 alkyl.
  • 1, 2, 3, or 4 of R 2A are independently C1-C6 alkoxy substituted with -NR A R B or 4-10 membered heterocyclyl. In some embodiments, 1, 2, 3, or 4 of R 2A are independently C1-C6 alkoxy. In some embodiments, 1, 2, 3, or 4 of R 2A are independently C3-C6 cycloalkyl optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, 1, 2, 3, or 4 of R 2A are independently C3-C6 cycloalkyl substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl.
  • 1, 2, 3, or 4 of R 2A are independently C3-C6 cycloalkyl substituted with 4-10 membered heterocyclyl substituted with C1-C6 alkyl. In some embodiments, 1, 2, 3, or 4 of R 2A are independently C3-C6 cycloalkyl substituted with 4-10 membered heterocyclyl. In some embodiments, 1, 2, 3, or 4 of R 2A are independently C3-C6 cycloalkyl. In some embodiments, 1 or 2 of R 2A are independently C3-C6 cycloalkyl. In some embodiments, R 2 is –O(R 2B ). In some embodiments, R 2B is phenyl optionally substituted with 1-4 independently selected R 2A .
  • R 2B is phenyl substituted with 1 or 2 independently selected R 2A . In some embodiments, R 2B is phenyl substituted with 1 R 2A . In some embodiments, R 2B is phenyl substituted with 2 independently selected R 2A . In some embodiments, R 2B is phenyl optionally substituted with 3 independently selected R 2A . In some embodiments, R 2B is phenyl. In some embodiments, R 2B is 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R 2A . In some embodiments, R 2B is 5-10 membered heteroaryl substituted with 1 or 2 independently selected R 2A .
  • R 2B is 5-10 membered heteroaryl substituted with 1 R 2A . In some embodiments, R 2B is 5-10 membered heteroaryl substituted with 2 independently selected R 2A . In some embodiments, R 2B is 5-10 membered heteroaryl optionally substituted with 3 independently selected R 2A . In some embodiments, R 2B is 5-10 membered heteroaryl.
  • the heteroaryl of R 2B is pyridinyl, pyrimidinyl, pyridazinyl, indole, indazole, azaindole, azaindazole, indoline, azaindoline, isoindoline, azaisoindoline, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzoisoxazolyl, benzisothiazolyl, quinolinyl, or isoquinolinyl.
  • the heteroaryl of R 2B is pyridinyl or pyrimidinyl.
  • the heteroaryl of R 2B is indole, indazole, azaindole, azaindazole, indoline, azaindoline, isoindoline, or azaisoindoline.
  • R 2B is 4-10 membered heterocyclyl optionally substituted with 1-4 independently selected R 2A .
  • R 2B is 4-10 membered heterocyclyl substituted with 1 or 2 independently selected R 2A .
  • R 2B is 4-10 membered heterocyclyl substituted with 1 R 2A .
  • R 2B is 4-10 membered heterocyclyl substituted with 2 independently selected R 2A .
  • R 2B is 4-10 membered heterocyclyl optionally substituted with 3 independently selected R 2A . In some embodiments, R 2B is 4-10 membered heterocyclyl. In some embodiments, R 2B is 5-8 membered heterocyclyl optionally substituted with 1-4 independently selected R 2A . In some embodiments, R 2B is 5-8 membered heterocyclyl substituted with 1 or 2 independently selected R 2A . In some embodiments, R 2B is 5-8 membered heterocyclyl substituted with 1 R 2A . In some embodiments, R 2B is 5-8 membered heterocyclyl substituted with 2 independently selected R 2A .
  • R 2B is 5-8 membered heterocyclyl optionally substituted with 3 independently selected R 2A . In some embodiments, R 2B is 5-8 membered heterocyclyl. In some embodiments, the heterocyclyl of R 2B is piperidinyl, piperazinyl, tetrahydropyranyl, or morpholinyl. In some embodiments, R 2B is 4-10 membered cycloalkyl optionally substituted with 1-4 independently selected R 2A . In some embodiments, R 2B is 4-10 membered cycloalkyl substituted with 1 or 2 independently selected R 2A . In some embodiments, R 2B is 4-10 membered cycloalkyl substituted with 1 R 2A .
  • R 2B is 4-10 membered cycloalkyl substituted with 2 independently selected R 2A . In some embodiments, R 2B is 4-10 membered cycloalkyl optionally substituted with 3 independently selected R 2A . In some embodiments, R 2B is 4-10 membered cycloalkyl. In some embodiments, the cycloalkyl of R 2B is cyclopentyl, [1.1.1]bicyclopentyl, or cyclohexyl. In some embodiments, R 2 is piperidinyl substituted with 1-2 independently selected R 2A . In some embodiments, R 2 is piperidinyl substituted with 2-4 independently selected R 2A .
  • R 2 is morpholinyl substituted with 2-4 independently selected R 2A . In some embodiments, R 2 is morpholinyl. In some embodiments, R 2 is piperazinyl substituted with 1-2 independently selected R 2A . In some embodiments, R 2 is phenyl substituted with 1-2 independently selected R 2A . In some embodiments, R 2 is indolyl substituted with 1-2 independently selected R 2A . In some embodiments, R 2 is indolyl substituted with 2 independently selected R 2A , where at least one R 2A is C1-C6 alkyl.
  • R 2 is indolyl substituted with 2 independently selected R 2A , where one R 2A is C1-C6 alkyl and one R 2A is 4-10 membered heterocyclyl.
  • R 2 is indazolyl substituted with 1-2 independently selected R 2A .
  • R 2 is 7-azaindolyl substituted with 1-2 independently selected R 2A .
  • R 2 is 7-azaindazolyl substituted with 1-2 independently selected R 2A .
  • R 2 is 1,2-dihydro-3H-indazol-3-one substituted with 1-2 independently selected R 2A .
  • R 2 is isoindolinyl substituted with 1-2 independently selected R 2A . In some embodiments, R 2 is isoindolinyl. In some embodiments, R 2 is 2- indolinone substituted with 1-2 independently selected R 2A . In some embodiments, R 2 is beznimidazolyl substituted with 1-2 independently selected R 2A . In some embodiments, R 2 is imidazopyridinyl substituted with 1-2 independently selected R 2A . In some embodiments, R 2 is 1,3-dihydro-2H-benzo[d]imidazol-2-onyl substituted with 1-2 independently selected R 2A .
  • R 2 is [1,2,4]triazolo[1,5-a]pyridine substituted with 1-2 independently selected R 2A .
  • R 2 is substituted with 1 R 2A .
  • R 2A is 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl and -NR A R B . In some embodiments, R 2A is 5-6 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl and -NR A R B .
  • R 2A is 4-10 membered heterocyclyl.
  • R 2A is C1-C6 alkyl.
  • R 2A is C1-C6 alkoxy.
  • R 2A is C3-C6 cycloalkyl optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl.
  • X is a bond. In some embodiments, X is CH 2 . In some embodiments, X is CH(CH 3 ). In some embodiments, X is C(CH 3 ) 2 . In some embodiments, X is In some embodiments, Z is O.
  • R 3A is hydrogen. In some embodiments, R 3A is C1-C6 alkyl. In some embodiments, R 3A is methyl or ethyl. In some embodiments, R 3A is methyl.
  • R 3A is C1-C6 alkoxy. In some embodiments, R 3A is C1-C3 alkoxy. In some embodiments, R 3A is –OCH 3 , -OCH 2 CH 3 , or –OCH 2 CH 2 CH 3 . In some embodiments, R 3A is –OCH 3 . In some embodiments, R 3A is C1-C6 haloalkyl. In some embodiments, R 3A is C1-C3 haloalkyl. In some embodiments, R 3A is C1-C3 fluoroalkyl. In some embodiments, R 3A is CF3. In some embodiments, R 3A is CHF2. In some embodiments, Z is NR 3B .
  • one of R 3A and R 3B is hydrogen and the other of R 3A and R 3B is C1-C6 alkyl. In some embodiments, one of R 3A and R 3B is hydrogen and the other of R 3A and R 3B is methyl. In some embodiments, each of R 3A and R 3B is hydrogen. In some embodiments, each of R 3A and R 3B is an independently selected C1-C6 alkyl. In some embodiments, each of R 3A and R 3B is methyl. In some embodiments, one of R 3A and R 3B is hydrogen and the other of R 3A and R 3B is C1-C6 alkoxy.
  • one of R 3A and R 3B is C1-C6 alkyl and the other of R 3A and R 3B is C1-C6 alkoxy. In some embodiments, R 3A is C1-C6 alkoxy. In some embodiments, R 3A is C1-C3 alkoxy. In some embodiments, R 3A is –OCH 3 , -OCH 2 CH 3 , or –OCH 2 CH 2 CH 3 . In some embodiments, R 3A is –OCH 3 . In some embodiments, one of R 3A and R 3B is hydrogen and the other of R 3A and R 3B is C1-C6 haloalkyl.
  • one of R 3A and R 3B is C1-C6 alkyl and the other of R 3A and R 3B is C1-C6 haloalkyl.
  • R 3A is C1-C6 haloalkyl.
  • R 3A is C1-C3 haloalkyl.
  • R 3A is C1-C3 fluoroalkyl.
  • R 3A is CF3.
  • R 3A is CHF2.
  • R 3A and R 3B together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group.
  • R 3A and R 3B together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 5-6 membered heterocyclyl group.
  • Y is phenyl optionally substituted with R Y , naphthyl substituted with R Y , or 5-10 membered heteroaryl substituted with R Y .
  • Y is phenyl optionally substituted with 1-3 independently selected R Y .
  • Y is phenyl substituted with 1 or 2 independently selected R Y .
  • Y is phenyl substituted with 1 R Y .
  • Y is phenyl substituted with 2 independently selected R Y . In some embodiments, Y is phenyl optionally substituted with 3 independently selected R Y . In some embodiments, Y is phenyl. In some embodiments, Y is naphthyl optionally substituted with 1-3 independently selected R Y . In some embodiments, Y is naphthyl substituted with 1 or 2 independently selected R Y . In some embodiments, Y is naphthyl substituted with 1 R Y . In some embodiments, Y is naphthyl substituted with 2 independently selected R Y . In some embodiments, Y is naphthyl optionally substituted with 3 independently selected R Y .
  • Y is naphthyl. In some embodiments, Y is 5-10 membered heteroaryl optionally substituted with 1-3 independently selected R Y . In some embodiments, Y is 5-10 membered heteroaryl substituted with 1 or 2 independently selected R Y . In some embodiments, Y is 5-10 membered heteroaryl substituted with 1 R Y . In some embodiments, Y is 5-10 membered heteroaryl substituted with 2 independently selected R Y . In some embodiments, Y is 5-10 membered heteroaryl optionally substituted with 3 independently selected R Y . In some embodiments, Y is 5-10 membered heteroaryl.
  • Y is 6 membered heteroaryl optionally substituted with 1-3 independently selected R Y . In some embodiments, Y is 6 membered heteroaryl substituted with 1 or 2 independently selected R Y . In some embodiments, Y is 6 membered heteroaryl substituted with 1 R Y . In some embodiments, Y is 6 membered heteroaryl substituted with 2 independently selected R Y . In some embodiments, Y is 6 membered heteroaryl optionally substituted with 3 independently selected R Y . In some embodiments, Y is 6 membered heteroaryl. In some embodiments, Y is 9 membered heteroaryl optionally substituted with 1-3 independently selected R Y .
  • Y is 9 membered heteroaryl substituted with 1 or 2 independently selected R Y . In some embodiments, Y is 9 membered heteroaryl substituted with 1 R Y . In some embodiments, Y is 9 membered heteroaryl substituted with 2 independently selected R Y . In some embodiments, Y is 9 membered heteroaryl optionally substituted with 3 independently selected R Y . In some embodiments, Y is 9 membered heteroaryl. In some embodiments, 1, 2, or 3 of R Y is independently halogen. In some embodiments, 1, 2, or 3 of R Y is independently chloro or fluoro. In some embodiments, 1 or 2 of R Y is independently chloro or fluoro.
  • 1, 2, or 3 of R Y is hydroxyl. In some embodiments, 1 or 2 of R Y is hydroxyl. In some embodiments, 1, 2, or 3 of R Y is cyano. In some embodiments, 1 or 2 of R Y is cyano. In some embodiments, 1, 2, or 3 of R Y is independently C1-C6 haloalkyl optionally substituted with hydroxyl. In some embodiments, 1, 2, or 3 of R Y is independently C1-C6 haloalkyl substituted with hydroxyl. In some embodiments, 1, 2, or 3 of R Y is independently C1- C6 haloalkyl. In some embodiments, 1 or 2 of R Y is independently C1-C3 haloalkyl.
  • 1 or 2 of R Y is trifluoromethyl. In some embodiments, 1, 2, or 3 of R Y is independently C1-C6 alkoxy. In some embodiments, 1 or 2 of R Y is independently C1-C3 alkoxy. In some embodiments, 1 or 2 of R Y is methoxy. In some embodiments, 1, 2, or 3 of R Y is independently C1-C6 haloalkoxy. In some embodiments, 1 or 2 of R Y is independently C1-C3 haloalkoxy. In some embodiments, 1 or 2 of R Y is trifluoromethoxy. In some embodiments, 1, 2, or 3 of R Y is independently C1-C6 hydroxyalkyl.
  • Y is substituted with 1 R Y , and R Y is –CO 2 R A . In some embodiments, Y is substituted with 1 R Y , and R Y is –CO 2 H. In some embodiments, 1, 2, or 3 of R Y is independently -SO 2 NR F R G . In some embodiments, 1 or 2 of R Y is independently -SO 2 NR F R G . In some embodiments, 1 of R Y is -SO 2 NR F R G . In some embodiments, Y is substituted with 1 R Y , and R Y is -SO 2 NR F R G . In some embodiments, 1, 2, or 3 of R Y is independently -NHSO 2 R F .
  • 1, 2, or 3 of R Y is independently –SO 2 (C1-C6 alkyl).
  • 1 or 2 of R Y is independently –SO 2 (C1-C6 alkyl).
  • 1 of R Y is –SO 2 (C1-C6 alkyl).
  • 1 or 2 of R Y is –SO 2 CH 3 .
  • 1 of R Y is –SO 2 CH 3 .
  • Y is substituted with 1 R Y , and R Y is –SO 2 CH 3 .
  • R Y is independently heteroaralkyl. In some embodiments, 1 of R Y is independently heteroaralkyl. In some embodiments, 1, 2, or 3 of R Y is independently 4-6 membered heterocyclyl optionally substituted with R Y1 . In some embodiments, 1 of R Y is 4-6 membered heterocyclyl. In some embodiments, 1 of R Y is 4-6 membered heterocyclyl substituted with R Y1 . In some embodiments, Y is substituted with 1 R Y , and R Y is 4-6 membered heterocyclyl substituted with R Y1 , where R Y1 is hydroxyl.
  • R Y is In some embodiments, R Y is In some embodiments, Y is selected from the group consisting of: , In some embodiments, 1, 2, or 3 of R Y is independently C1-C6 alkyl optionally substituted with –CO 2 R A or 4-6 membered heteroaryl optionally substituted with R Y1 . In some embodiments, 1, 2, or 3 of R Y is independently C1-C6 alkyl substituted with –CO 2 R A or 4-6 membered heteroaryl optionally substituted with R Y1 . In some embodiments, 1, 2, or 3 of R Y is independently C1-C6 alkyl substituted with –CO 2 R A or 4-6 membered heteroaryl substituted with R Y1 .
  • R Y is independently C1-C6 alkyl substituted with –CO 2 R A or 4-6 membered heteroaryl.
  • Y is substituted with 1 R Y
  • R Y is C1-C6 alkyl substituted with –CO 2 R A .
  • Y is substituted with 1 R Y
  • R Y is C1-C6 alkyl substituted with –CO 2 H.
  • 1 or 2 of R Y is independently C1-C6 alkyl optionally substituted with –CO 2 R A or 4-6 membered heteroaryl optionally substituted with R Y1 .
  • 1 or 2 of R Y is independently C1-C6 alkyl substituted with –CO 2 R A or 4-6 membered heteroaryl optionally substituted with R Y1 . In some embodiments, 1 or 2 of R Y is independently C1-C6 alkyl substituted with –CO 2 R A or 4-6 membered heteroaryl substituted with R Y1 . In some embodiments, 1 or 2 of R Y is independently C1-C6 alkyl substituted with – CO 2 R A or 4-6 membered heteroaryl. In some embodiments, 1 or 2 of R Y is independently C1-C6 alkyl substituted with – CO 2 R A .
  • 1 or 2 of R Y is independently C1-C6 alkyl substituted 4-6 membered heteroaryl optionally substituted with R Y1 . In some embodiments, 1 or 2 of R Y is independently C1-C6 alkyl substituted with 4-6 membered heteroaryl substituted with R Y1 . In some embodiments, 1 or 2 of R Y is independently C1-C6 alkyl substituted with 4-6 membered heteroaryl. In some embodiments, Y is substituted with 1 R Y . In some embodiments, Y is substituted with 2 independently selected R Y . In some embodiments, Y is substituted with 3 independently selected R Y . In some embodiments, Y is substituted with 1 R Y .
  • R Y is 4-6 membered heterocyclyl optionally substituted with R Y1 .
  • R Y is C1-C6 alkyl optionally substituted with –CO 2 R A or 4-6 membered heteroaryl optionally substituted with R Y1 .
  • 1, 2, or 3 of R Y is independently C1-C6 alkyl.
  • 1 or 2 of R Y is independently C1-C3 alkyl.
  • 1, 2, or 3 of R Y is methyl.
  • R Y1 is –SO 2 (C1-C6 alkyl).
  • R Y1 is – SO 2 CH 3 .
  • R Y1 is C1-C6 alkyl optionally substituted with oxo. In some embodiments, R Y1 is C1-C6 alkyl substituted with oxo. In some embodiments, R Y1 is acetyl, 1- oxoethyl, or 1-oxopropyl. In some embodiments, R Y1 is C1-C6 alkyl. In some embodiments, R Y1 is methyl. In some embodiments, R Y1 is hydroxyl. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is C1-C6 alkyl. In some embodiments, R 4 is methyl or ethyl. In some embodiments, R 4 is methyl.
  • R 4 is acrylamido.
  • R 5 is hydrogen.
  • R 5 is C1-C6 alkyl.
  • R 5 is methyl or ethyl.
  • R 5 is methyl.
  • R 5 is cyano.
  • R 5 is -NR 5A R 5B .
  • one of R 5A and R 5B is hydrogen and the other of R 5A and R 5B is C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 hydroxyalkyl. In some embodiments, one of R 5A and R 5B is C1-C6 alkyl and the other of R 5A and R 5B is C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 hydroxyalkyl. In some embodiments, each of R 5A and R 5B is hydrogen. In some embodiments, each of R 5A and R 5B is an independently selected C1-C6 alkyl. In some embodiments, each of R 5A and R 5B is methyl.
  • the C1-C6 hydroxyalkyl of R 5A and R 5B is hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, dihydroxypropyl or dihydroxybutyl.
  • R 5 is acrylamido.
  • R 6 is hydrogen.
  • R 6 is halogen.
  • R 6 is fluoro.
  • R 6 is chloro.
  • R 6 is C1-C6 alkyl. In some embodiments, R 6 is methyl.
  • each of R A and R B are independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy.
  • one of R A and R B is hydrogen and the other of R A and R B is hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, or C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy.
  • one of R A and R B is hydrogen and the other of R A and R B is hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, or C1-C6 alkyl substituted with hydroxyl or C1-C6 alkoxy.
  • one of R A and R B is hydrogen and the other of R A and R B is hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, or C1-C6 alkyl.
  • one of R A and R B is hydrogen and the other of R A and R B is hydroxyl.
  • one of R A and R B is hydrogen and the other of R A and R B is C1-C6 alkoxy. In some embodiments, one of R A and R B is hydrogen and the other of R A and R B is C3-C6 cycloalkyl. In some embodiments, one of R A and R B is hydrogen and the other of R A and R B is C2-C6 alkenyl. In some embodiments, one of R A and R B is hydrogen and the other of R A and R B is C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy. In some embodiments, one of R A and R B is hydrogen and the other of R A and R B is C1-C6 alkyl substituted with hydroxyl.
  • one of R A and R B is hydrogen and the other of R A and R B is C1-C6 alkyl substituted with C1-C6 alkoxy. In some embodiments, one of R A and R B is hydrogen and the other of R A and R B is C1- C6 alkyl. In some embodiments, each of R A and R B are hydrogen. In some embodiments, each of R A and R B are an independently selected C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy. In some embodiments, each of R A and R B are an independently selected C1-C6 alkyl. In some embodiments, each of R A and R B are methyl.
  • R A and R B together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl substituted with 1-2 substitutents independently selected from fluoro, methyl, and acetyl.
  • R A and R B together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl.
  • R A and R B together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl.
  • each R C is independently C1-C6 alkyl substituted with -NR A R B or with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl.
  • one of R D and R E is hydrogen and the other of R D and R E is hydroxyl, C1-C6 alkyl, or C1-C6 alkoxy.
  • one of R D and R E is hydrogen and the other of R D and R E is hydroxyl.
  • one of R D and R E is hydrogen and the other of R D and R E is C1-C6 alkyl.
  • one of R D and R E is hydrogen and the other of R D and R E is C1-C6 alkoxy. In some embodiments, one of R D and R E is hydrogen and the other of R D and R E is hydroxyl, methyl, or methoxy. In some embodiments, each of R D and R E is hydrogen. In some embodiments, each of R D and R E is an independently selected C1-C6 alkyl. In some embodiments, each of R D and R E is methyl. In some embodiments, one of R F and R G is hydrogen and the other of R F and R G is phenyl or C1-C6 alkyl optionally substituted with oxo or –NR A R B .
  • one of R F and R G is hydrogen and the other of R F and R G is phenyl or C1-C6 alkyl substituted with oxo or –NR A R B . In some embodiments, one of R F and R G is hydrogen and the other of R F and R G is phenyl or C1-C6 alkyl. In some embodiments, one of R F and R G is hydrogen and the other of R F and R G is phenyl. In some embodiments, one of R F and R G is hydrogen and the other of R F and R G is C1-C6 alkyl optionally substituted with oxo or –NR A R B .
  • one of R F and R G is hydrogen and the other of R F and R G is C1-C6 alkyl substituted with oxo or –NR A R B .
  • each of R F and R G is hydrogen.
  • each of R F and R G is an independently selected C1-C6 alkyl.
  • each of R F and R G is methyl.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is a compound of Formula (I-A1): or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is a compound of Formula (I-AA):
  • the compound of Formula (I), or pharmaceutically acceptable salt thereof is a compound of Formula (I-B): or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I), or pharmaceutically acceptable salt thereof is a compound of Formula (I-C): or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I), or pharmaceutically acceptable salt thereof is a compound of Formula (I-D): or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I), or pharmaceutically acceptable salt thereof is a compound of Formula (I-E):
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is a compound of Formula (I-F): or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is a compound of Formula (I-FF): or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is a compound of Formula (I-G):
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is a compound of Formula (I-G1): or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is a compound of Formula (I-G2): or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is a compound of Formula (I-G3):
  • the compound of Formula (I), or pharmaceutically acceptable salt thereof is a compound of Formula (I-G4): or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I), or pharmaceutically acceptable salt thereof is a compound of Formula (I-G5): or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I), or pharmaceutically acceptable salt thereof is a compound of Formula (I-G6): or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is a compound of Formula (I-H): or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 5-6 membered heterocyclyl or 5-6 membered heteroaryl; Q is N or CH; m is 0, 1, 2, or 3; n is 0, 1, or 2; and m+n is 0, 1, 2, or 3.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is a compound of Formula (I-HH): or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 5-6 membered heterocyclyl or 5-6 membered heteroaryl; Q is N or CH; m is 0, 1, 2, or 3; n is 0, 1, or 2; and m+n is 0, 1, 2, or 3.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is a compound of Formula (I-I): or a pharmaceutically acceptable salt thereof, wherein: Ring B is a 5-6 membered heterocyclyl, 6 membered heteroaryl, or phenyl; m is 0, 1, 2, or 3; n is 0, 1, or 2; and m+n is 0, 1, 2, or 3.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is a compound of Formula (I-II): or a pharmaceutically acceptable salt thereof, wherein: Ring B is a 5-6 membered heterocyclyl, 6 membered heteroaryl, or phenyl; m is 0, 1, 2, or 3; n is 0, 1, or 2; and m+n is 0, 1, 2, or 3.
  • Ring B is a 5-6 membered heterocyclyl, 6 membered heteroaryl, or phenyl
  • m is 0, 1, 2, or 3
  • n is 0, 1, or 2
  • m+n is 0, 1, 2, or 3.
  • Non-Limiting Exemplary Compounds the compound is selected from the group consisting of the Compounds 1-1413, or a pharmaceutically acceptable salt thereof.
  • the compound is selected from the group consisting of the compounds delineated in Table A, or a pharmaceutically acceptable salt thereof.
  • compositions Some embodiments provide a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • a “PI3K ⁇ inhibitor” as used herein includes any compound exhibiting PI3K ⁇ inactivation activity (e.g., inhibiting or decreasing).
  • a PI3K ⁇ inhibitor can be selective for a PI3K ⁇ having one or more mutations. The ability of test compounds to act as inhibitors of PI3K ⁇ may be demonstrated by assays known in the art.
  • the activity of the compounds and compositions provided herein as PI3K ⁇ inhibitors can be assayed in vitro, in vivo, or in a cell line.
  • In vitro assays include assays that determine inhibition of the kinase. Alternate in vitro assays quantitate the ability of the inhibitor to bind to the protein kinase and can be measured either by radio labeling the compound prior to binding, isolating the compound/kinase complex and determining the amount of radio label bound, or by running a competition experiment where new compounds are incubated with the kinase bound to known radio ligands. Potency of a PI3K ⁇ inhibitor as provided herein can be determined by EC 50 value.
  • a compound with a lower EC 50 value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher EC 50 value.
  • Potency of a PI3K ⁇ inhibitor as provided herein can also be determined by IC 50 value.
  • a compound with a lower IC 50 value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher IC 50 value.
  • the substantially similar conditions comprise determining a PI3K ⁇ -dependent phosphorylation level, in vitro or in vivo.
  • the selectivity between wild type PI3K ⁇ and PI3K ⁇ containing one or more mutations as described herein can also be measured using in vitro assays such as surface plasmon resonance and fluorence-based binding assays, and cellular assays such as the levels of pAKT, a biomarker of PI3K ⁇ activity, and/or proliferation assays where cell proliferation is dependent on mutant PI3K ⁇ kinase activity.
  • the compounds provided herein can exhibit potent and selective inhibition of PI3K ⁇ .
  • the compounds provided herein can bind to the helical phosphatidylinositol kinase homology domain catalytic domain of PI3K ⁇ .
  • the compounds provided herein can exhibit nanomolar potency against a PI3K ⁇ kinase including one or more mutations, for example, the mutations in Table 1.
  • the compounds of Formula (I), or a pharmaceutically acceptable salt thereof can selectively target PI3K ⁇ .
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can selectively target PI3K ⁇ over another kinase or non-kinase target.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can exhibit greater inhibition of PI3K ⁇ containing one or more mutations as described herein (e.g., one or more mutations as described in Table 1) relative to inhibition of wild type PI3K ⁇ .
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or 100-fold greater inhibition of PI3K ⁇ containing one or more mutations as described herein relative to inhibition of wild type PI3K ⁇ .
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can exhibit up to 1,000-fold greater inhibition of PI3K ⁇ containing one or more mutations as described herein relative to inhibition of wild type PI3K ⁇ . In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit up to 10,000-fold greater inhibition of PI3K ⁇ having a combination of mutations described herein relative to inhibition of wild type PI3K ⁇ . In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit from about 2-fold to about 10-fold greater inhibition of PI3K ⁇ containing one or more mutations as described herein relative to inhibition of wild type PI3K ⁇ .
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can exhibit from about 10-fold to about 100-fold greater inhibition of PI3K ⁇ containing one or more mutations as described herein relative to inhibition of wild type PI3K ⁇ . In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit from about 100-fold to about 1,000-fold greater inhibition of PI3K ⁇ containing one or more mutations as described herein relative to inhibition of wild type PI3K ⁇ .
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can exhibit from about 1000-fold to about 10,000-fold greater inhibition of PI3K ⁇ containing one or more mutations as described herein relative to inhibition of wild type PI3K ⁇ .
  • Compounds of Formula (I), or pharmaceutically acceptable salts thereof are useful for treating diseases which can be treated with a PI3K ⁇ inhibitor, such as PI3K ⁇ -associated diseases, e.g., proliferative disorders such as cancers, including hematological cancers and solid tumors (e.g., advanced or metastatic solid tumors).
  • the subject has been identified or diagnosed as having a cancer with a dysregulation of a PIK3CA gene, a PI3K ⁇ protein, or expression or activity, or level of any of the same (a PI3K ⁇ -associated cancer), for example, as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit.
  • the subject has a tumor that is positive for a dysregulation of a PIK3CA gene, a PI3K ⁇ protein, or expression or activity, or level of any of the same (e.g., as determined using a regulatory agency-approved assay or kit).
  • the subject has a tumor that is positive for a mutation as described in Table 1.
  • the subject can be a subject with a tumor(s) that is positive for a dysregulation of a PIK3CA gene, a PI3K ⁇ protein, or expression or activity, or level of any of the same (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit).
  • the subject can be a subject whose tumors have a dysregulation of a PIK3CA gene, a PI3K ⁇ protein, or expression or activity, or a level of the same (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay).
  • the subject is suspected of having a PI3K ⁇ -associated cancer.
  • the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of a PIK3CA gene, a PI3K ⁇ protein, or expression or activity, or level of any of the same (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein).
  • compounds of Formula (I), or pharmaceutically acceptable salts thereof are useful for preventing diseases as defined herein such as cancer.
  • the term “preventing” as used herein means to delay the onset, recurrence or spread, in whole or in part, of the disease as described herein, or a symptom thereof.
  • PI3K ⁇ -associated disease refers to diseases associated with or having a dysregulation of a PIK3CA gene, a PI3K ⁇ protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a PIK3CA gene, or a PI3K ⁇ protein, or the expression or activity or level of any of the same described herein).
  • Non-limiting examples of a PI3K ⁇ -associated disease include, for example, proliferative disorders such as cancer (e.g., PI3K ⁇ -associated cancer).
  • PI3K ⁇ -associated cancer refers to cancers associated with or having a dysregulation of a PIK3CA gene, a PI3K ⁇ protein, or expression or activity, or level of any of the same. Non-limiting examples of PI3K ⁇ -associated cancer are described herein.
  • the phrase “dysregulation of a PIK3CA gene, a PI3K ⁇ protein, or the expression or activity or level of any of the same” refers to a genetic mutation (e.g., a mutation in a PIK3CA gene that results in the expression of a PI3K ⁇ that includes a deletion of at least one amino acid as compared to a wild type PI3K ⁇ , a mutation in a PIK3CA gene that results in the expression of PI3K ⁇ with one or more point mutations as compared to a wild type PI3K ⁇ , a mutation in a PIK3CA gene that results in the expression of PI3K ⁇ with at least one inserted amino acid as compared to a wild type PI3K ⁇ , a gene duplication that results in an increased level of PI3K ⁇ in a cell, or a mutation in a regulatory sequence (e.g., a promoter and/or enhancer) that results in an increased level of PI3K ⁇ in a cell
  • a dysregulation of a PIK3CA gene, a PI3K ⁇ protein, or expression or activity, or level of any of the same can be a mutation in a PIK3CA gene that encodes a PI3K ⁇ that is constitutively active or has increased activity as compared to a protein encoded by a PIK3CA gene that does not include the mutation.
  • Non- limiting examples of PI3K ⁇ point mutations/substitutions/insertions/deletions are described in Table 1.
  • wild type describes a nucleic acid (e.g., a PIK3CA gene or a PI3K ⁇ mRNA) or protein (e.g., a PI3K ⁇ ) sequence that is typically found in a subject that does not have a disease related to the reference nucleic acid or protein.
  • a nucleic acid e.g., a PIK3CA gene or a PI3K ⁇ mRNA
  • protein e.g., a PI3K ⁇ sequence that is typically found in a subject that does not have a disease related to the reference nucleic acid or protein.
  • wild type PI3K ⁇ or “wild-type PI3K ⁇ ” describes a normal PI3K ⁇ nucleic acid (e.g., a PIK3CA or PI3K ⁇ mRNA) or protein that is found in a subject that does not have a PI3K ⁇ -associated disease, e.g., a PI3K ⁇ -associated cancer (and optionally also does not have an increased risk of developing a PI3K ⁇ -associated disease and/or is not suspected of having a PI3K ⁇ -associated disease), or is found in a cell or tissue from a subject that does not have a PI3K ⁇ -associated disease, e.g., a PI3K ⁇ -associated cancer (and optionally also does not have an increased risk of developing a PI3K ⁇ -associated disease and/or is not suspected of having a PI3K ⁇ -associated disease).
  • a PI3K ⁇ -associated disease e.g., a PI3K ⁇ -associated
  • a method of treating cancer comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • methods for treating PI3K ⁇ -associated cancer in a subject in need thereof comprising a) detecting a dysregulation of PIK3CA gene, a PI3K ⁇ protein, or the expression or activity or level of any of the same in a sample from the subject; and b) administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the dysregulation of a PIK3CA gene, a PI3K ⁇ protein, or the expression or activity or level of any of the same includes one or more a PI3K ⁇ protein substitutions/point mutations/insertions.
  • PI3K ⁇ protein substitutions/insertions/deletions are described in Table 1.
  • the PI3K ⁇ protein substitution/insertion/deletion is selected from the group consisting of E542A, E542G, E542K, E542Q, E542V, E545A, E545D, E545G, E545K, E545Q, M1043I, M1043L, M1043T, M1043V, H1047L, H1047Q, H1047R, H1047Y, G1049R, and combinations thereof.
  • the PI3K ⁇ protein substitution / insertion / deletion is H1047X, where X is any amino acid other than H.
  • the PI3K ⁇ protein substitution / insertion / deletion is E542X, where X is any amino acid other than E. In some embodiments, the PI3K ⁇ protein substitution / insertion / deletion is E545X, where X is any amino acid other than E.
  • the dysregulation of a PIK3CA gene, a PI3K ⁇ protein, or expression or activity or level of any of the same includes a splice variation in a PI3K ⁇ mRNA which results in an expressed protein that is an alternatively spliced variant of PI3K ⁇ having at least one residue deleted (as compared to the wild type PI3K ⁇ protein) resulting in a constitutive activity of a PI3K ⁇ protein domain.
  • the dysregulation of a PIK3CA gene, a PI3K ⁇ protein, or expression or activity or level of any of the same includes at least one point mutation in a PIK3CA gene that results in the production of a PI3K ⁇ protein that has one or more amino acid substitutions or insertions or deletions in a PIK3CA gene that results in the production of a PI3K ⁇ protein that has one or more amino acids inserted or removed, as compared to the wild type PI3K ⁇ protein.
  • the resulting mutant PI3K ⁇ protein has increased activity, as compared to a wild type PI3K ⁇ protein or a PI3K ⁇ protein not including the same mutation.
  • the compounds described herein selectively inhibit the resulting mutant PI3K ⁇ protein relative to a wild type PI3K ⁇ protein or a PI3K ⁇ protein not including the same mutation.
  • the cancer e.g., PI3K ⁇ -associated cancer
  • the cancer is selected from a hematological cancer and a solid tumor.
  • the cancer e.g., PI3K ⁇ -associated cancer
  • breast cancer including both HER2 + and HER2- breast cancer, ER + breast cancer, and triple negative breast cancer
  • uterine cancer including endometrial cancer
  • lung cancer including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLS, including adenocarcinoma lung cancer and squamous cell lung carcinoma)
  • esophageal squamous cell carcinoma ovarian cancer, colorectal cancer, esophagastric adenocarcinoma, bladder cancer, head and neck cancer (including head and neck squamous cell cancers such as oropharyngeal squamous cell carcinoma), thyroid cancer, glioma, cervical cancer, lymphangioma, meningioma, melanoma (including uveal melanoma), kidney cancer, pancreatic neuroendocine neoplasm
  • the cancer e.g., PI3K ⁇ -associated cancer
  • breast cancer including both HER2 + and HER2- breast cancer, ER + breast cancer, and triple negative breast cancer
  • colon cancer rectal cancer, colorectal cancer, ovarian cancer, lymphangioma, meningioma, head and neck squamous cell cancer (including oropharyngeal squamous cell carcinoma), melanoma (including uveal melanoma), kidney cancer, pancreatic neuroendocine neoplasms (pNETs), stomach cancer, esophageal cancer, acute myeloid leukemia, relapsed and refractory multiple myeloma, pancreatic cancer, lung cancer (including adenocarcinoma lung cancer and squamous cell lung carcinoma), and endometrial cancer.
  • breast cancer including both HER2 + and HER2- breast cancer, ER + breast cancer, and triple negative breast cancer
  • rectal cancer colorectal cancer
  • the cancer e.g., PI3K ⁇ -associated cancer
  • the cancer is selected from breast cancer, SCLC, NSCLC, endometrial cancer, esophageal squamous cell carcinoma, ovarian cancer, colorectal cancer, esophagastric adenocarcinoma, bladder cancer, head and neck cancer, thyroid cancer, glioma, and cervical cancer.
  • the PI3K ⁇ -associated cancer is breast cancer. In some embodiments of any of the methods or uses described herein, the PI3K ⁇ -associated cancer is colorectal cancer. In some embodiments of any of the methods or uses described herein, the PI3K ⁇ -associated cancer is endometrial cancer. In some embodiments of any of the methods or uses described herein, the PI3K ⁇ -associated cancer is lung cancer.
  • the PI3K ⁇ - associated cancer is selected from the cancers described in Table 1.
  • the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject having a cell having aberrant PI3K ⁇ activity.
  • the cell is a cancer cell. In some embodiments, the cancer cell is any cancer as described herein. In some embodiments, the cancer cell is a PI3K ⁇ -associated cancer cell.
  • the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • contacting includes the administration of a compound provided herein to an individual or subject, such as a human, having a PI3K ⁇ protein, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the PI3K ⁇ protein.
  • a method of inhibiting cell proliferation, in vitro or in vivo comprising contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.
  • a method of increase cell death, in vitro or in vivo comprising contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.
  • a method of increasing tumor cell death in a subject comprising administering to the subject an effective compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount effective to increase tumor cell death.
  • the PI3K ⁇ is human PI3K ⁇ .
  • the PI3K ⁇ has one or more point mutations in the PIK3CA gene.
  • the point mtations include a substitution at amino acid position 1047 of a human PI3K ⁇ protein.
  • the substitution is H1047R.
  • the compounds of Formula (I), including pharmaceutically acceptable salts thereof can be administered in the form of pharmaceutical compositions as described herein. Embodiments 1.
  • R 1 is hydrogen, cyano, C3-C6 cycloalkyl, C1-C6 alkyl optionally substituted with phenyl optionally substituted with halogen, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 alkoxyalkyl;
  • the compound of any one of Embodiments 1-48, wherein 1, 2, 3, or 4 of R 2A are independently C1-C6 alkoxy substituted with -NR A R B or 4-10 membered heterocyclyl substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or –C( O)C3-C6 cycloalkyl. 50.
  • 51. The compound of any one of Embodiments 1-47, wherein 1, 2, 3, or 4 of R 2A are independently C1-C6 alkoxy. 52.
  • R 2 is C1-C6 alkoxyalkyl.
  • 62 The compound of any one of Embodiments 1-61, wherein X is a bond.
  • 63 The compound of any one of Embodiments 1-61, wherein X is CH 2 .
  • 64 The compound of any one of Embodiments 1-61, wherein X is CH(CH 3 ).
  • 65 The compound of any one of Embodiments 1-61, wherein X is C(CH 3 ) 2 .
  • 66 The compound of any one of Embodiments 1-61, wherein X is . 67.
  • Z is O. 68.
  • 76. The compound of Embodiment 73, wherein each of R 3A and R 3B is hydrogen.
  • the compound of Embodiment 73, wherein each of R 3A and R 3B is an independently selected C1-C6 alkyl.
  • 78. The compound of Embodiment 73 or 77, wherein each of R 3A and R 3B is methyl. 79.
  • each of R D and R E is an independently selected C1-C6 alkyl. 145.
  • each of R F and R G is hydrogen.
  • each of R F and R G is an independently selected C1-C6 alkyl.
  • 150. A compound selected from the group consisting of the compounds in Table A, or a pharmaceutically acceptable salt thereof.
  • 151. A pharmaceutical composition comprising a compound of any one of Embodiments 1-150, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. 152.
  • a method for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1-150, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 151.
  • a method for treating cancer in a subject in need thereof comprising (a) determining that the cancer is associated with a dysregulation of a PIK3CA gene, a PI3K ⁇ protein, or expression or activity or level of any of the same; and (b) administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1-150, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 151.
  • a method of treating a PI3K ⁇ -associated cancer in a subject comprising administering to a subject identified or diagnosed as having a PI3K ⁇ -associated cancer a therapeutically effective amount of a compound of any one of Embodiments 1-150 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 151.
  • a method for inhibiting mutant PI3K ⁇ activity in a mammalian cell comprising contacting the mammalian cell with an effective amount of a compound of any one of Embodiments 1-150, or a pharmaceutically acceptable salt thereof.
  • the starting materials used for the syntheses are either synthesized or obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, Fluka, Acros Organics, Alfa Aesar, Enamine, Strem, VWR Scientific, and the like.
  • Nuclear Magnetic Resonance (NMR) analysis was conducted using a Bruker AVANCE III HD (300 or 400) MHz spectrometer or Bruker AVANCE NEO 400 MHz spectrometer with an appropriate deuterated solvent.
  • LCMS spectra were obtained on a Shimadzu LCMS-2020 with electrospray ionization in positive ion detection mode with 20ADXR pump, SIL-20ACXR autosampler, CTO-20AC column oven, M20A PDA Detector and LCMS 2020 MS detector.
  • Example 1 Preparation of rel-(R)-2-((1-(7-methyl-4-oxo-2-(pyridin-4-yl)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 268) and rel-(R)-2-((1- (7-methyl-4-oxo-2-(pyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 269) Step 1: Preparation of rel-(R)-2-((1-(7-methyl-4-oxo-2-(pyridin-4-yl)-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 268) and rel-(R)-2-((1-(7-methyl-4-oxo- 2-(pyridin-4-yl)
  • Step 2 Synthesis of 2-(benzyloxy)-9-bromo-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one
  • a solution of 9-bromo-2-hydroxy-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (12.5 g, 49 mmol), K 2 CO 3 (13.5 g, 98 mmol) and TBAI (1.8 mg, 4.9 mmol) in DMF (120 mL) was added BnBr (6.71 g, 39.2 mmol). The reaction was heated to 65 oC for 2 h under N 2 atmosphere.
  • Step 3 Synthesis of 9-acetyl-2-(benzyloxy)-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one
  • 2-(benzyloxy)-9-bromo-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (3 g, 8.7 mmol)
  • tributyl(1-ethoxyvinyl)stannane 7.85 g, 21.7 mmol
  • Pd(dppf)Cl 2 509 mg, 0.7 mmol
  • the reaction mixture was stirred at 90 °C for 16 h under N 2 atmosphere.
  • Step 4 Synthesis of 9-(1-aminoethyl)-2-(benzyloxy)-7-methyl-4H-pyrido[1,2- a]pyrimidin-4-one
  • NH 4 OAc 3.75 g, 48.6 mmol
  • MeOH 10 mL
  • NaBH 3 CN 610 mg, 9.7 mmol
  • Step 5 Synthesis of tert-butyl 2-((1-(2-(benzyloxy)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate
  • a mixture of 9-(1-aminoethyl)-2-(benzyloxy)-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one 500 mg, 1.6 mmol
  • tert-butyl 2-bromobenzoate 540 mg, 2.1 mmol
  • Cs 2 CO 3 (1.05 g, 3.2 mmol)
  • Pd 2 (dba) 3 148 mg, 0.16 mmol
  • Xantphos 140 mg, 0.24 mmol
  • Step 7 Synthesis of tert-butyl 2-((1-(7-methyl-4-oxo-2-(((trifluoromethyl)sulfonyl)oxy)- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate
  • a solution of tert-butyl 2-((1-(2-hydroxy-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin- 9-yl)ethyl)amino)benzoate 500 mg, 1.3 mmol
  • DCM 10 mL
  • pyridine 300 mg, 3.8 mmol
  • Tf 2 O 535 mg, 1.9 mmol
  • Step 8 Synthesis of tert-butyl 2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-7-methyl-4-oxo- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate
  • tert-butyl 2-((1-(7-methyl-4-oxo-2-(((trifluoromethyl)sulfonyl)oxy)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate 300 mg, 569 umol
  • K 2 CO 3 (236 mg, 1.7 mmol)
  • 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (217 mg, 796 umol) (prepared according to the procedure in WO201755305) in dioxane
  • the reaction mixture was heated to 100 °C and stirred for 2 h under N 2 atmosphere.
  • the reaction was diluted with water (20 mL) and ethyl acetate (20 mL x 3).
  • the combined organic phase was washed with brine (20 mL x 2), dried over anhydrous Na 2 SO 4 , filtered and concentrated.
  • the crude residue was purified by flash chromatography on silica gel eluting with (3% MeOH in DCM) to afford the title compound (290 mg, 97%) as a yellow solid.
  • Step 9 Synthesis of 2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid
  • a mixture of tert-butyl 2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate 50 mg, 95 umol
  • DCM 3 mL
  • TFA 0.5 mL, 6.9 mmol
  • reaction mixture was stirred at room temperature for 16 h.
  • the mixture was concentrated and the residue was purified by reverse phase chromatography (acetonitrile 51% - 81% / 0.225% formic acid in water) to give the title compound (5 mg, 11%) as a white solid.
  • Step 10 Synthesis of (R)-2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 739) and (S)-2-((1-(2-(1,3- dimethyl-1H-indazol-5-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (Compound 740) 2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (200 mg, 428 umol)
  • Step 2 Synthesis of 2-((1-(2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-7- methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid To a mixture of tert-butyl 2-((1-(2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-7- methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (140 mg, 0.26 mmol) in DCM (3 mL) was added TFA (1 mL).
  • Step 3 Synthesis of 2-((R)-1-(2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-7- methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 711) and 2-(((S)-1-(2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 712) 2-((1-(2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-7-methyl-4-oxo-4H- pyri
  • Step 2 Synthesis of 2-(benzyloxy)-9-bromo-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4- one
  • a mixture of 9-bromo-2-hydroxy-3,7-dimethyl-pyrido[1,2-a]pyrimidin-4-one (10 g, 37.2 mmol), K 2 CO 3 (10.3 g, 74.3 mmol) and TBAI (1.37 g, 3.72 mmol) in DMF (100 mL) was added (bromomethyl)benzene (3.53 mL, 29.7 mmol). The mixture was stirred at 65 °C for 4 h under N 2 atmosphere.
  • Step 3 Synthesis of 9-acetyl-2-(benzyloxy)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4- one
  • a mixture of 2-(benzyloxy)-9-bromo-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (20 g, 55.7 mmol) and Pd(dppf)Cl 2 (2.04 g, 2.78 mmol) in dioxane (200 mL) was degassed and purged with N 2 for 3 times, and then tributyl(1-ethoxyvinyl)stannane (40.2 g, 111 mmol) was added, the final mixture was stirred at 90 °C for 16 h under N 2 atmosphere.
  • Step 4 Synthesis of 9-(1-aminoethyl)-2-(benzyloxy)-3,7-dimethyl-4H-pyrido[1,2- a]pyrimidin-4-one
  • a mixture of 9-acetyl-2-benzyloxy-3,7-dimethyl-pyrido[1,2-a]pyrimidin-4-one (8 g, 24.8 mmol), NH 4 OAc (28.7 g, 372 mmol), NaBH 3 CN (4.68 g, 74.45 mmol) and AcOH (1.42 mL, 24.82 mmol) in MeOH (100 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 50 °C for 4 h under N 2 atmosphere.
  • Step 5 Synthesis of tert-butyl 2-((1-(2-(benzyloxy)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate
  • a mixture of 9-(1-aminoethyl)-2-(benzyloxy)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin- 4-one (15.1 g, 46.7 mmol)
  • tert-butyl 2-bromobenzoate (18.0 g, 70.0 mmol)
  • Cs 2 CO 3 (30.4 g, 93.4 mmol)
  • Pd 2 (dba) 3 (2.05 g, 2.24 mmol
  • Xantphos (2.70 g, 4.67 mmol) in dioxane (200 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 100
  • Step 6 Synthesis of tert-butyl 2-((1-(2-hydroxy-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate
  • a mixture of tert-butyl 2-((1-(2-(benzyloxy)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (5 g, 10.0 mmol), Pd/C (2.72 g, 2.00 mmol, 10% purity) in MeOH (15 mL) was degassed and purged with H 2 (15 psi) for 3 times, and then the mixture was stirred at room temperature for 1 h under H 2 atmosphere.
  • Step 7 Synthesis of tert-butyl 2-((1-(3,7-dimethyl-4-oxo-2- (((trifluoromethyl)sulfonyl)oxy)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate
  • a solution of tert-butyl 2-((1-(2-hydroxy-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate 0.6 g, 1.47 mmol
  • DCM 15 mL
  • pyridine pyridine
  • Tf 2 O 363 uL, 2.20 mmol
  • Step 8 Synthesis of tert-butyl 2-((1-(2-(4-fluorophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate
  • tert-butyl 2-((1-(3,7-dimethyl-4-oxo-2-(((trifluoromethyl)sulfonyl)oxy)- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate 100 mg, 0.19 mmol
  • K 2 CO 3 77 mg, 0.55 mmol
  • (4-fluorophenyl)boronic acid 78 mg, 0.55 mmol
  • Step 9 Synthesis of 2-((1-(2-(4-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 721)
  • To a solution of tert-butyl 2-((1-(2-(4-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate 60 mg, 0.13 mmol
  • DCM 3 mL
  • TFA 0.2 mL, 26 mmol
  • the reaction mixture was stirred at room temperature for 16 h.
  • the solution was adjusted pH to 10 with aq. LiOH (2 M), then adjusted pH to 6 with formic acid.
  • the crude residue was purified by reverse phase chromatography (acetonitrile 65-95% / 0.225% formic acid in water) to afford the title compound (15 mg, 28%) as a yellow solid.
  • Step 2 Synthesis of 2-(benzyloxy)-9-(1-bromoethyl)-7-methyl-4H-pyrido[1,2- a]pyrimidin-4-one
  • PBr 3 6-(1-hydroxyethyl)-7-methyl-pyrido[1,2-a]pyrimidin-4-one
  • Step 3 Synthesis of 2-((1-(2-(benzyloxy)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzenesulfonamide
  • 2-benzyloxy-9-(1-bromoethyl)-7-methyl-pyrido[1,2-a]pyrimidin-4-one 500 mg, 1.34 mmol
  • 2-aminobenzenesulfonamide (1.38 g, 8 mmol) at room temperature.
  • the reaction was stirred at 100 oC for 2 h under N 2 atmosphere. After cooling to room temperature, the mixture was concentrated in vacuo.
  • Step 4 Synthesis of 2-((1-(2-hydroxy-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzenesulfonamide: To a solution of 2-[1-(2-benzyloxy-7-methyl-4-oxo-pyrido[1,2-a]pyrimidin-9- yl)ethylamino]benzenesulfonamide (370 mg, 796 umol) in MeOH (5 mL) was added palladium on carbon (250 mg, 239 umol). The reaction was stirred at room temperature for 2 h under a hydrogen atmosphere.
  • Step 6 Synthesis of (R)-2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzenesulfonamide & (S)-2-((1-(2-(isoindolin-2-yl)-7-methyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzenesulfonamide 2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzenesulfonamide (100 mg, 0.21 mmol) was separated by using chiral SFC (DAICEL CHIRALCEL AD (250mm*30mm,10um); Supercritical CO 2 / EtOH
  • Step 1 Synthesis of tert-butyl (3aR,6aS)-5,5-difluorohexahydrocyclopenta[c]pyrrole- 2(1H)-carboxylate
  • DCM dimethyl methoxycarbonate
  • Step 2 Synthesis of (3aR,6aS)-5,5-difluorooctahydrocyclopenta[c]pyrrole trifluoroacetate
  • a solution of tert-butyl (3aR,6aS)-5,5-difluorohexahydrocyclopenta[c]pyrrole-2(1H)- carboxylate 450 mg, 1.82 mmol
  • DCM DCM
  • TFA 1.04 g, 9 mmol
  • Step 3 Synthesis of tert-butyl 2-((1-(2-((3aR,6aS)-5,5-difluorohexahydrocyclopenta[c] pyrrol-2(1H)-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate
  • a solution of tert-butyl 2-[1-(2-hydroxy-7-methyl-4-oxo-pyrido[1,2-a]pyrimidin-9- yl)ethylamino]benzoate 180 mg, 45 umol
  • DMF 5 mL
  • DIEA DIEA (0.24 mL, 1.81 mmol
  • Step 4 2-((1-(2-((3aR,6aS)-5,5-difluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-7- methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid
  • Step 5 Synthesis of 2-(((R)-1-(2-((3aR,6aS)-5,5-difluorohexahydrocyclopenta[c]pyrrol- 2(1H)-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 582) and 2-(((S)-1-(2-((3aR,6aS)-5,5-difluorohexahydrocyclopenta[c]pyrrol-2(1H)- yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 583) 2-((1-(2-((3aR,6aS)-5,5-difluorohexahydrocyclopenta[c]pyrrol- 2(1H)-y
  • Step 2 Synthesis of tert-butyl (R)-2-((1-(2-(3-amino-1-methyl-1H-indazol-5-yl)-7- methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate & tert-butyl (S)-2-((1-(2- (3-amino-1-methyl-1H-indazol-5-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoate tert-butyl 2-((1-(2-(3-amino-1-methyl-1H-indazol-5-yl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (125 mg, 238 umol) was separated
  • Step 3 Synthesis of (S)-2-((1-(2-(3-amino-1-methyl-1H-indazol-5-yl)-7-methyl-4-oxo- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 536) To a mixture of tert-butyl (S)-2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-7-methyl-4-oxo- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (60 mg, 114 umol) in DCM (3 mL) was added TFA (1 mL).
  • Example 12 Preparation of (S)-2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 393) Step 1 - tert-butyl 2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate To a solution of tert-butyl 2-((1-(2-hydroxy-7-methyl- 4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (150 mg, 379 umol) in DMF (2 mL) was added DIEA (198 uL, 1.14 mmol) and PyBOP (236 mg, 455 umol).
  • Step 3 (R)-2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid & (S)-2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 403) 2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (100 mg, 227 umol) was separated by using chiral SFC (DAICEL CHIRALCEL OJ-H (250mm*30mm,5um); Supercritical CO 2 / EtOH + 0.1% NH 3
  • Step 2 Synthesis of 9-(1-ethoxyvinyl)-2-(isoindolin-2-yl)-7-methyl-4H-pyrido[1,2- a]pyrimidin-4-one: A mixture of 9-bromo-2-(isoindolin-2-yl)-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (6.5 g, 18 mmol), tributyl(1-ethoxyvinyl)stannane (14 g, 39 mmol), Pd(dppf)Cl 2 (668 mg, 912 umol) in dioxane (100 mL) was stirred at 100 °C for 16 h under N 2 atmosphere.
  • Step 3 Synthesis of 9-acetyl-2-(isoindolin-2-yl)-7-methyl-4H-pyrido[1,2- a]pyrimidin-4-one
  • THF 10 mL
  • 1M HCl 5 mL
  • the reaction mixture was stirred at room temperature for 3 hours.
  • the mixture was adjusted to pH 7 with sat. aq. NaHCO 3 , then extracted with EtOAc (60 mL x 2).
  • Step 4 Synthesis of 9-(1-hydroxyethyl)-2-(isoindolin-2-yl)-7-methyl-4H-pyrido[1,2- a]pyrimidin-4-one
  • MeOH MeOH
  • NaBH 4 142 mg, 3.76 mmol
  • Step 5 Synthesis of 9-(1-bromoethyl)-2-(isoindolin-2-yl)-7-methyl-4H-pyrido[1,2- a]pyrimidin-4-one
  • PBr 3 1.6 g, 5.91 mmol
  • Step 6 Synthesis of 2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzamide
  • a mixture of 9-(1-bromoethyl)-2-(isoindolin-2-yl)-7-methyl-4H-pyrido[1,2-a]pyrimidin- 4-one (100 mg, 260 umol) and 2-aminobenzamide (71 mg, 520 umol) in dioxane (1 mL) was stirred at 100 °C for 2 hours. After cooling to room temperature, the mixture was concentrated in vacuo.
  • Step 2 Synthesis of 2-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid trifluoroacetate (Compound 764)
  • To a solution of tert-butyl 2-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (30 mg, 59 umol) in DCM (1.5 mL) was added TFA (0.5 ml).
  • Step 2 Synthesis of 2-((1-(2-(4,4-dimethyl-1,4-azasilinan-1-yl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid
  • tert-butyl 2-((1-(2-(4,4-dimethyl-1,4-azasilinan-1-yl)-7-methyl-4-oxo- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate 150 mg, 296 umol
  • DCM 6 mL
  • TFA 2 mL
  • reaction mixture was stirred at 110 °C for 2 h under N 2 atmosphere. After cooling to room temperature, the reaction was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 20% EtOAc in petroleum ether) to give 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2(3H)- one (1.4 g, 93%) as a yellow solid.
  • Step 2 Synthesis of tert-butyl 2-((1-(7-methyl-4-oxo-2-(2-oxo-2,3- dihydrobenzo[d]thiazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate
  • tert-butyl 2-((1-(7-methyl-4-oxo-2-(((trifluoromethyl)sulfonyl)oxy)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate 150 mg, 284 umol
  • 5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2(3H)-one 158 mg, 569 umol) in dioxane (2 mL) and water (0.2 mL) was added K 2 CO 3
  • reaction mixture was heated to 100 °C and stirred for 2 hours under N 2 atmosphere. After cooling to room temperature, the reaction was diluted with water (20 mL) and EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step 2 Synthesis of 2-((1-(2-(4-fluorophenyl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid
  • TFA 0.5 mL
  • Step 2 Synthesis of tert-butyl 2-((1-(2-(1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5- yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate
  • tert-butyl 2-((1-(7-methyl-4-oxo-2-(((trifluoromethyl)sulfonyl)oxy)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (193 mg, 366 umol), 1,3-dimethyl-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridine (200 mg, 732 umol), K 2 CO 3 (152 mg, 1.10 mmol) in di
  • reaction mixture was stirred at 100 °C for 2 hours under N 2 atmosphere. After cooling to room temperature, the mixture was diluted with EtOAc (60 mL), washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step 3 Synthesis of tert-butyl (R)-2-((1-(2-(1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin- 5-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate & tert-butyl (S)-2-((1-(2-(1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate tert-butyl 2-((1-(2-(1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethy
  • Step 2 Synthesis of 2-((1-(2-(1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-3,7- dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid
  • To a mixture of tert-butyl 2-((1-(2-(1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-3,7- dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate 34 mg, 63 umol
  • DCM 3 mL
  • Step 2 Synthesis of 1,2,3-trimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrrolo[2,3-b]pyridine
  • Pd(dppf)Cl 2 306 mg, 418.22 ⁇ mol
  • KOAc 1,4-dioxaborolan-2-yl-1,3,2-dioxaborolane
  • Step 3 Synthesis of tert-butyl 2-((1-(3,7-dimethyl-4-oxo-2-(1,2,3-trimethyl-1H- pyrrolo[2,3-b]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate
  • a solution of tert-butyl 2-((1-(3,7-dimethyl-4-oxo-2-(((trifluoromethyl)sulfonyl)oxy)- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate 190 mg, 349 ⁇ mol
  • K 2 CO 3 145 mg, 1.05 mmol
  • 1,2,3-trimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3- b]pyridine 200 mg, 699
  • Step 4 Synthesis of 2-((1-(3,7-dimethyl-4-oxo-2-(1,2,3-trimethyl-1H-pyrrolo[2,3- b]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid
  • a mixture of tert-butyl 2-((1-(3,7-dimethyl-4-oxo-2-(1,2,3-trimethyl-1H-pyrrolo[2,3- b]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate 13 mg, 24 umol
  • DCM mL
  • TFA 0.5 mL
  • Example 23 Preaparation of 2-(isoindolin-2-yl)-7-methyl-9-(1-((2-(pyridazin-4- yl)phenyl)amino)ethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (Compound 665) Step 1 - Synthesis of 9-(1-((2-bromophenyl)amino)ethyl)-2-(isoindolin-2-yl)-7- methyl-4H-pyrido[1,2-a]pyrimidin-4-one A mixture of 9-(1-bromoethyl)-2-(isoindolin-2-yl)-7-methyl-4H-pyrido[1,2-a]pyrimidin- 4-one (50 mg, 0.13 mmol) and 2-bromoaniline (112 mg, 0.65 mmol) in dioxane (1 mL) was heated to 100 °C
  • Step 3 Synthesis of 2-((1-(2-(4,4-dimethylcyclohexyl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid
  • a solution of tert-butyl 2-((1-(2-(4,4-dimethylcyclohexyl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate 100 mg, 204 umol
  • TFA 1,2-a]pyrimidin-9-yl
  • Step 2 Synthesis of tert-butyl 2-(((R)-1-(2-((3R,5S)-3,5-dimethylpiperidin-1-yl)-7- methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate and tert-butyl 2-(((S)- 1-(2-((3R,5S)-3,5-dimethylpiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoate tert-butyl 2-((1-(2-((3R,5S)-3,5-dimethylpiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (80 mg, 137
  • Step 2 Synthesis of 9-acetyl-2-(isoindolin-2-yl)-3,7-dimethyl-4H-pyrido[1,2- a]pyrimidin-4-one
  • a solution of 9-bromo-2-isoindolin-2-yl-3,7-dimethyl-pyrido[1,2-a]pyrimidin-4-one (5.2 g, 14.0 mmol) in dioxane (60 mL) was added Pd(dppf)Cl 2 (514 mg, 702 umol) and tributyl(1-ethoxyvinyl)stannane (9.5 mL, 28.0 mmol). The mixture was stirred at 90 °C for 16 hours under N 2 atmosphere.
  • Step 3 Synthesis of 9-(1-hydroxyethyl)-2-(isoindolin-2-yl)-3,7-dimethyl-4H- pyrido[1,2-a]pyrimidin-4-one
  • a solution of 9-acetyl-2-isoindolin-2-yl-3,7-dimethyl-pyrido[1,2-a]pyrimidin-4-one (3.5 g, 10.5 mmol) in MeOH (40 mL) was added NaBH 4 (1.2 g, 31.5 mmol) at 0 °C.
  • the mixture was stirred at room temperature for 16 hours under N 2 atmosphere.
  • the reaction was quenched with 1M HCl (10 mL) at 0°C.
  • Step 4 Synthesis of 9-(1-bromoethyl)-2-(isoindolin-2-yl)-3,7-dimethyl-4H- pyrido[1,2-a]pyrimidin-4-one
  • PBr 3 847 mg, 3.13 mmol
  • Step 5 Synthesis of 9-(1-((2-bromophenyl)amino)ethyl)-2-(isoindolin-2-yl)-3,7- dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one
  • a mixture of 9-(1-bromoethyl)-2-(isoindolin-2-yl)-3,7-dimethyl-4H-pyrido[1,2- a]pyrimidin-4-one (100 mg, 251 umol) and 2-bromoaniline (86 mg, 502 umol) in dioxane (1 mL) was stirred at 90 °C for 2 hours. After cooling to room temperature, the mixture was concentrated in vacuo.
  • Step 6 Synthesis of 2-(isoindolin-2-yl)-3,7-dimethyl-9-(1-((2-(pyridazin-4- yl)phenyl)amino) ethyl)-4H-pyrido[1,2-a]pyrimidin-4-one
  • To a solution of 9-(1-((2-bromophenyl)amino)ethyl)-2-(isoindolin-2-yl)-3,7-dimethyl- 4H-pyrido[1,2-a]pyrimidin-4-one (130 mg, 266 ⁇ mol) in dioxane (2 mL) was added Pd(dppf)Cl 2 (19 mg, 27 ⁇ mol), Na 2 CO 3 (84 mg, 797 ⁇ mol) and tributyl(pyridazin-4-yl)stannane (103 mg, 279 ⁇ mol).
  • Step 2 Synthesis of 2-(isoindolin-2-yl)-3,7-dimethyl-9-(1-((2-(pyridazin-4- yl)thiophen-3-yl)amino)ethyl)-4H-pyrido[1,2-a]pyrimidin-4-one
  • To a solution of 9-(1-((2-bromothiophen-3-yl)amino)ethyl)-2-(isoindolin-2-yl)-3,7- dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (20 mg, 40 ⁇ mol) in dioxane (2 mL) was added Pd(PPh 3 ) 2 Cl 2 (3 mg, 4 ⁇ mol), Na 2 CO 3 (13 mg, 120 ⁇ mol) and tributyl(pyridazin-4-yl)stannane (30 mg, 81 ⁇ mol).
  • Step 1 Synthesis of 2-((1-(2-(1,3-dimethyl-1H-indol-5-yl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate
  • tert-butyl 2-((1-(3,7-dimethyl-4-oxo-2-(((trifluoromethyl)sulfonyl)oxy)- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate 200 mg, 369 ⁇ mol
  • K 2 CO 3 153 mg, 1.11 mmol
  • 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole 100 mg, 369 ⁇ mol
  • Step 2 Synthesis of 2-((1-(2-(1,3-dimethyl-1H-indol-5-yl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid
  • 2-((1-(2-(1,3-dimethyl-1H-indol-5-yl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate 150 mg, 280 ⁇ mol
  • DCM 4- mL
  • TFA 2 mL
  • Step 2 Synthesis of 2-((1-(2-(3-cyano-4-fluorophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid Following the procedure described in Example 33, Step 2 and making non-critical variations as required to replace tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate with tert-butyl 2-((1-(2-(3-cyano-4- fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate, 2-((1- (2-(3-cyano-4-fluorophenyl
  • Step 3 Synthesis of (R)-2-((1-(2-(3-cyano-4-fluorophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid & (S)-2-((1-(2-(3-cyano-4- fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid 2-((1-(2-(3-cyano-4-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (50 mg, 110 ⁇ mol) was separated by using chiral SFC (DAICEL CHIRALCEL OJ (250mm*30mm,10um
  • Step 2 Synthesis of 2-((1-(2-(4-chlorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid Following the procedure described in Example 33, Step 2 and making non-critical variations as required to replace tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate with tert-butyl 2-((1-(2-(4-chlorophenyl)-3,7- dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate, 2-((1-(2-(4- chlorophen
  • Step 2 Synthesis of 2-((1-(2-(4-chloro-2-fluorophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid Following the procedure described in Example 33, Step 2 and making non-critical variations as required to replace tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate with tert-butyl 2-((1-(2-(4-chloro-2- fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate, 2-((1-(2-(4-chloro-2- fluoroph
  • Step 2 Synthesis of 2-((1-(2-(6-cyanopyridin-3-yl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid Following the procedure described in Example 33, Step 2 and making non-critical variations as required to replace tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate with tert-butyl 2-((1-(2-(6-cyanopyridin-3- yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate, 2-((1-(2-(6-cyanopyridin-3- yl)
  • Example 38 Preparation of 2-((1-(3,7-dimethyl-4-oxo-2-(pyridin-4-yl)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 1408) Step 1 - Synthesis of tert-butyl 2-((1-(3,7-dimethyl-4-oxo-2-(pyridin-4-yl)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate Following the procedure described in Example 33, Step 1 and making non-critical variations as required to replace (3-cyanophenyl)boronic acid with pyridin-4-ylboronic acid, tert- butyl 2-((1-(3,7-dimethyl-4-oxo-2-(pyridin-4-yl)-4H-pyrido[1,2-a]
  • Step 2 Synthesis of 2-((1-(3,7-dimethyl-4-oxo-2-(pyridin-4-yl)-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid Following the procedure described in Example 33, Step 2 and making non-critical variations as required to replace tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate with tert-butyl 2-((1-(3,7-dimethyl-4-oxo-2- (pyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate, 2-((1-(3,7-dimethyl-4-dimethyl-4-oxo-2- (pyridin-4-
  • Step 2 Synthesis of 2-((1-(2-(3-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid Following the procedure described in Example 33, Step 2 and making non-critical variations as required to replace tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate with tert-butyl 2-((1-(2-(3-fluorophenyl)-3,7- dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate, 2-((1-(2-(3- fluorophenyl)-3,7-dimethyl-4-oxo
  • Step 2 Synthesis of 2-((1-(2-(3-(difluoromethyl)phenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid Following the procedure described in Example 33, Step 2 and making non-critical variations as required to replace tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate with tert-butyl 2-((1-(2-(3- (difluoromethyl)phenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoate, 2-((1-(2-(3-(difluoromethyl
  • Step 3 Synthesis of (R)-2-((1-(2-(3-(difluoromethyl)phenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 1077) & (S)-2-((1-(2-(3- (difluoromethyl)phenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid 2-((1-(2-(3-(difluoromethyl)phenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (90 mg, 194 ⁇ mol) was separated by using chiral SFC (DAICEL CHIRALCEL
  • Example 41 Preparation of (R)-2-((1-(2-(5-chloro-6-methylpyridin-3-yl)-3,7- dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 951) Step 1 - Synthesis of tert-butyl 2-((1-(2-(5-chloro-6-methylpyridin-3-yl)-3,7-dimethyl- 4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate Following the procedure described in Example 33, Step 1 and making non-critical variations as required to replace (3-cyanophenyl)boronic acid with (5-chloro-6-methylpyridin-3- yl)boronic acid, tert-butyl 2-((1-(2-(5-chloro-6-methylpyridin-3-yl)-3,7-d
  • Step 2 Synthesis of 2-((1-(2-(5-chloro-6-methylpyridin-3-yl)-3,7-dimethyl-4-oxo- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid Following the procedure described in Example 33, Step 2 and making non-critical variations as required to replace tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate with tert-butyl 2-((1-(2-(5-chloro-6- methylpyridin-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate, 2-((1-(2-(5-chloro
  • Step 2 Synthesis of 2-((1-(2-(3-cyclopropylphenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid Following the procedure described in Example 33, Step 2 and making non-critical variations as required to replace tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate with tert-butyl 2-((1-(2-(3- cyclopropylphenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate, 2-((1-(2-(3- cyclopropylphenyl)-3,7
  • Step 2 Synthesis of 2-((1-(2-(5-chloro-6-cyanopyridin-3-yl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid Following the procedure described in Example 33, Step 2 and making non-critical variations as required to replace tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate with tert-butyl 2-((1-(2-(5-chloro-6- cyanopyridin-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino
  • Example 47 Preparation of 9-(1-((3-hydroxybenzo[d]isoxazol-4-yl)amino)ethyl)-3,7- dimethyl-2-(pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (Compound 1365) Step 1 – Synthesis of 9-chloro-2-hydroxy-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4- one A solution of 3-chloro-5-methylpyridin-2-amine (5 g, 35 mmol) in acetone (60 mL) was added bis(2,4,6-trichlorophenyl) 2-methylmalonate (18.4 g, 38.6 mmol).
  • Step 2 Synthesis of 9-chloro-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl trifluoromethanesulfonate
  • pyridine 2.9 mL, 36 mmol
  • Tf 2 O 2.38 mL, 14.4 mmol
  • Step 3 Synthesis of 9-chloro-3,7-dimethyl-2-(pyridin-3-yl)-4H-pyrido[1,2- a]pyrimidin-4-one
  • a mixture of 9-chloro-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl trifluoromethanesulfonate (6 g, 16.8 mmol), pyridin-3-ylboronic acid (2.27 mg, 18.5 mmol), Pd(PPh 3 ) 4 (972 mg, 841 ⁇ mol) and Na 2 CO 3 (5.35 g, 50.5 mmol) in dioxane (100 mL) and H 2 O (10 mL).
  • Step 4 Synthesis of 9-acetyl-3,7-dimethyl-2-(pyridin-3-yl)-4H-pyrido[1,2- a]pyrimidin-4-one
  • a mixture of 9-chloro-3,7-dimethyl-2-(pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 950 mg, 3.32 mmol
  • tributyl(1-ethoxyvinyl)stannane 3.49 g, 9.66 mmol
  • SPhos Pd G 3 129.7 mg, 166 umol
  • CsF (1.01 g, 6.65 mmol
  • the reaction mixture was stirred at 100 °C for 16 h under N 2 atmosphere. After cooling to room temperature, HCl (6 mL, 1 M) was added. The mixture was stirred at room temperature for 0.5 h. The reaction mixture was added 15 mL 10% KF aqueous solution, stirred at room temperature for 2 h. The mixture was extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give the title compound (400 mg, 67%) as a yellow solid.
  • Step 5 Synthesis of 9-(1-aminoethyl)-3,7-dimethyl-2-(pyridin-3-yl)-4H-pyrido[1,2- a]pyrimidin-4-one
  • NH 4 OAc 526 mg, 6.8 mmol
  • AcOH 41 mg, 681 umol, 236 ⁇ L
  • MeOH 4 mL
  • NaBH 3 CN 129 mg, 2.08 mmol
  • Step 6 Synthesis of 4-((1-(3,7-dimethyl-4-oxo-2-(pyridin-3-yl)-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)-2-(2,4,6-trimethoxybenzyl)benzo[d]isoxazol-3(2H)-one
  • 4-bromo-2-(2,4,6-trimethoxybenzyl)benzo[d] isoxazol-3(2H)-one 56 mg, 142 umol
  • Step 7 Synthesis of 9-(1-((3-hydroxybenzo[d]isoxazol-4-yl)amino)ethyl)-3,7- dimethyl-2-(pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-4-one
  • 4-((1-(3,7-dimethyl-4-oxo-2-(pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin- 9-yl)ethyl)amino)-2-(2,4,6-trimethoxybenzyl)benzo[d]isoxazol-3(2H)-one (30 mg, 49 umol) in DCM (1.5 mL) was added TFA (0.5 mL) and triisopropylsilane (8.60 mg, 54 ⁇ mol).
  • Example 48 Preparation of 2-(3-fluorophenyl)-9-(1-((2-(3-hydroxyisoxazol-5- yl)phenyl)amino)ethyl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (Compound 1367) Step 1 - Synthesis of 9-(1-aminoethyl)-2-(3-fluorophenyl)-3,7-dimethyl-4H- pyrido[1,2-a]pyrimidin-4-one Following the procedure described in Example 47 Step 3 - Step 5 and making non-critical variations as required to replace pyridin-3-ylboronic acid with (3-fluorophenyl) boronic acid, the title compound (2 g, crude) was obtained as a yellow solid.
  • Step 2 Synthesis of 9-(1-((2-bromophenyl)amino)ethyl)-2-(3-fluorophenyl)-3,7- dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one
  • a mixture of 9-(1-aminoethyl)-2-(3-fluorophenyl)-3,7-dimethyl-4H-pyrido[1,2- a]pyrimidin-4-one (1.64 g, 5.3 mmol), 1-bromo-2-iodo-benzene (2.24 g, 7.9 mmol,), Xantphos (610 mg, 1.1 mmol), Pd 2 (dba) 3 (482 mg, 527 ⁇ mol) and Cs 2 CO 3 (5.15 g, 15.8 mmol) in dioxane (25 mL) was heated to 100 °C and stirred for 16 h under N
  • Step 3 Synthesis of methyl 3-(2-((1-(2-(3-fluorophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)phenyl)propiolate
  • a mixture of 9-(1-aminoethyl)-2-(3-fluorophenyl)-3,7-dimethyl-4H-pyrido[1,2- a]pyrimidin-4-one 300 mg, 643 ⁇ mol
  • methyl prop-2-ynoate 216 mg, 2.6 mmol
  • Pd(PPh 3 ) 2 Cl 2 45 mg, 64 ⁇ mol
  • CuI 61 mg, 322 ⁇ mol
  • K 2 CO 3 267 mg, 1.9 mmol
  • Step 4 Synthesis of 2-(3-fluorophenyl)-9-(1-((2-(3-hydroxyisoxazol-5- yl)phenyl)amino)ethyl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one
  • methyl 3-(2-((1-(2-(3-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)phenyl)propiolate 34 mg, 72 ⁇ mol
  • EtOH 2 mL
  • hydroxylamine 10 mg, 144 ⁇ mol, 50% in water
  • Step 2 Synthesis of 9-acetyl-2-(3-fluorophenyl)-3,7-dimethyl-pyrido[1,2- a]pyrimidin-4-one
  • a mixture of 9-chloro-2-(3-fluorophenyl)-3,7-dimethyl-pyrido[1,2-a]pyrimidin-4-one (3.3 g, 10.90 mmol), CsF (3.3 g, 21.80 mmol) and Sphos Pd G3 (850 mg, 1.09 mmol) in toluene (40 mL) was degassed and purged with N 2 for 3 times, and then tributyl(1-ethoxyvinyl)stannane (8.3 g, 22.89 mmol) was added, the final mixture was stirred at 100 °C for 16 h under N 2 atmosphere.
  • Step 3 Synthesis of 9-(1-aminoethyl)-2-(3-fluorophenyl)-3,7-dimethyl-pyrido[1,2- a]pyrimidin-4-one
  • NH 4 OAc 8.72 g, 113.1 mmol
  • AcOH 452.83 mg, 7.5 mmol, 432 ⁇ L
  • MeOH 40 mL
  • reaction was heated to 60 °C for 3 h under N 2 atmosphere. After cooling to room temperature, the reaction mixture was diluted with EtOAc (100 mL). The mixture was washed with saturated NaHCO 3 solution (30 mL x 3), brine (30 mL), dried over anhydrous Na 2 SO 4 and filtered. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 15% MeOH in EtOAc (contain 0.1% NH 3 ⁇ H 2 O)) to give the title compound (700 mg, 30%) as yellow oil.
  • Step 4 Synthesis of 4-((1-(2-(3-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)-2-(2,4,6-trimethoxybenzyl)benzo[d]isoxazol-3(2H)-one
  • a mixture of 9-(1-aminoethyl)-2-(3-fluorophenyl)-3,7-dimethyl-pyrido[1,2-a]pyrimidin- 4-one (221 mg, 710 ⁇ mol), 4-bromo-2-(2,4,6-trimethoxybenzyl)benzo[d] isoxazol-3(2H)-one (200 mg, 507 ⁇ mol) (prepared according to the procedure in Eur.
  • Step 5 Synthesis of (R)-4-((1-(2-(3-fluorophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)-2-(2,4,6-trimethoxybenzyl)benzo[d]isoxazol- 3(2H)-one & (S)-4-((1-(2-(3-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)-2-(2,4,6-trimethoxybenzyl)benzo[d]isoxazol-3(2H)-one 4-((1-(2-(3-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)a
  • Example 52 2-(3-fluorophenyl)-9-(1-((2-(3-hydroxyoxetan-3- yl)phenyl)amino)ethyl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (Compound 1389) Step 1 – Synthesis of 2-(3-fluorophenyl)-9-(1-((2-iodophenyl)amino)ethyl)-3,7- dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one A mixture of 9-(1-aminoethyl)-2-(3-fluorophenyl)-3,7-dimethyl-4H-pyrido[1,2- a]pyrimidin-4-one (3.3 g, 10.6 mmol), 1,2-diiodobenzene (6.99 g, 21.2 mmol), Xantphos (613 mg, 1.1 mmol), Pd 2 (d
  • Step 2 Synthesis of 2-(3-fluorophenyl)-9-(1-((2-(3-hydroxyoxetan-3- yl)phenyl)amino)ethyl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one
  • 2-(3-fluorophenyl)-9-(1-((2-iodophenyl)amino)ethyl)-3,7-dimethyl-4H- pyrido[1,2-a]pyrimidin-4-one (0.14 g, 0.27 mmol) and oxetan-3-one (37 mg, 0.51 mmol) in THF (4 mL) was added n-BuLi (0.11 ml, 0.27 mmol, 2.5 M in n-hexane ) at -78 °C under N 2 atmosphere.
  • Step 2 Synthesis of 2-(3-fluorophenyl)-9-(1-(2-iodophenoxy)ethyl)-3,7-dimethyl-4H- pyrido[1,2-a]pyrimidin-4-one
  • 2-(3-fluorophenyl)-9-(1-hydroxyethyl)-3,7-dimethyl-4H-pyrido[1,2- a]pyrimidin-4-one 680 mg, 2.18 mmol
  • 2-iodophenol 718 mg, 3.27 mmol
  • DIAD 660 mg, 3.27 mmol
  • Step 3 Synthesis of 2-(3-fluorophenyl)-9-(1-(2-(3-hydroxythietan-3- yl)phenoxy)ethyl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one
  • 2-(3-fluorophenyl)-9-(1-(2-iodophenoxy)ethyl)-3,7-dimethyl-4H- pyrido[1,2-a]pyrimidin-4-one 0.6 g, 1.17 mmol
  • thietan-3-one 204 mg, 2.31 mmol
  • ASSAY PI3Ka cellular assay experimental procedure SKBR3 or T47D cells are seeded in DMEM containing 10% FBS at 25k cells/well into 96-well cell culture format. Cells are incubated overnight at 37°C in a 5% CO2 incubator and the following day cell media is aspirated, adherent cells are washed 1X with room temperature PBS prior to serum-free media application. Cells are returned to 37°C 5% CO2 incubator and incubated a further 16hrs. Compounds are added to serum starved adherent cells with a top dose of 10,000nM and 3x multiple dose reductions for a minimum dose of 0.5nM diluted in DMSO.
  • ND denotes value not determined with that assay for the specified compound
  • T47D (H1047R) selectivity over SKBR3 (WT) A denotes > 20-fold; B denotes 20- fold ⁇ value > 5-fold; C denotes ⁇ 5-fold.
  • ND denotes value not determined with that assay for the specified compound
  • T47D pAKT lipophilic efficiency (LiPE) A denotes > 4; B denotes 4 ⁇ value > 2; C denotes ⁇ 2.
  • ND denotes value not determined with that assay for the specified compound .
  • Table 1

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Abstract

This disclosure provides compounds of Formula (I) and pharmaceutically acceptable salts thereof, that inhibit phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Kα). These compounds are useful for treating a disease in which increased PI3Kα activation contributes to the pathology, symptoms, and/or progression of the disease (e.g., cancer) in a subject.

Description

4H-PYRIDO[1,2-A]PYRIMIDIN-4-ONE DERIVATIVES FOR TREATING CANCER CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Application No. 63/416,311, filed on October 14, 2022, the contents of which is hereby incorporated by reference in its entireties. SEQUENCE LISTING This application contains a Sequence Listing that has been submitted electronically as an XML file named “49366-0037WO1_ST26_SL.XML.” The XML file, created on October 13, 2023, is 2,933 bytes in size. The material in the XML file is hereby incorporated by reference in its entirety. TECHNICAL FIELD This disclosure provides compounds of Formula (I) and pharmaceutically acceptable salts thereof, that inhibit phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Kα). These compounds are useful for treating a disease in which increased PI3Kα activation contributes to the pathology, symptoms, and/or progression of the disease (e.g., cancer) in a subject. BACKGROUND Phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Kα), encoded by the PIK3CA gene is a part of the PI3K/AKT/TOR signaling network and is altered in several human cancers. Activation of the PI3K pathway occurs in approximately 30–50% human cancers and contributes to resistance to various anti-cancer therapies. (See, Bauer, T.M. et al., Pharmacol. Ther. 2015, 146, 53–60.) However, development of PI3K inhibitors has been problematic for several reasons, in particular, inability to specifically inhibit signaling by mutant PI3Kα while sparing wild-type PI3Kα, and the related dose-limiting toxicities that prevent sustained PI3K pathway suppression. (See, Hanker et al., Cancer Discovery, April 2019;9: 482-491.) For example, alpelisib is a PI3K inhibitor that is equipotent against wild-type and mutant forms of PI3Kα, which results in dose-limiting toxicities and hyperglycemia. Thus, selectively targeting PI3Kα represents an approach for the treatment of proliferative disorders such as cancer. SUMMARY Some embodiments provide a compound of Formula (I):
Figure imgf000003_0001
or a pharmaceutically acceptable salt thereof, wherein: R1 is hydrogen, cyano, C3-C6 cycloalkyl, C1-C6 alkyl optionally substituted with phenyl optionally substituted with halogen, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 alkoxyalkyl; R2 is phenyl optionally substituted with 1-4 independently selected R2A, 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R2A, 4-10 membered heterocyclyl optionally substituted with 1-4 independently selected R2A, 4-10 membered cycloalkyl optionally substituted with 1-4 independently selected R2A, C1-C6 alkoxyalkyl optionally substituted with –C(=O)NRARC, C1-C6 alkoxy optionally substituted with –C(=O)NRARC, or –O(R2B); each R2A is independently selected from: (i) halogen, (ii) cyano, (iii) hydroxyl, (iv) -NRARB, (v) -C(=O)NRARB, (vi)
Figure imgf000003_0002
(vii) -NHC(=O)RC, (viii) -C(=O)NRDRE, (ix) -C(=O)ORF, (x) -SO2RF, (xi) -NHSO2RF, (xii) -SO2NRFRG, (xiii) -NHC(=O)C1-C6 alkyl optionally substituted with NRARB, (xiv) C1-C6 haloalkyl, (xv) C1-C6 hydroxyalkyl, (xvi) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl and -NRARB, (xvii) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, -C(=O)NRARB, -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB, or C1- C6 alkyl optionally substituted with C1-C6 alkoxy or -NHC(=O)C1-C6 alkyl optionally substituted with C3-C16 cycloalkyl, (xviii) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C1-C6 alkoxy, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or –C(=O)C3-C6 cycloalkyl, (xix) C1-C6 alkoxy optionally substituted with -NRARB or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or –C(=O)C3-C6 cycloalkyl, and (xx) C3-C6 cycloalkyl optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl; R2B is phenyl optionally substituted with 1-4 independently selected R2A, 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R2A, 4-10 membered heterocyclyl optionally substituted with 1-4 independently selected R2A, 4-10 membered cycloalkyl optionally substituted with 1-4 independently selected R2A; each RA and RB is independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3- C6 cycloalkyl, C2-C6 alkenyl, –SO2(C1-C6 alkyl), and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy, or RA and RB together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C1-C6 alkyl, and –C(=O)C1-C6 alkyl; each RC is independently selected from C3-C6 cycloalkyl, -C(=O)NHRY1, or a C1-C6 alkyl optionally substituted with -NRARB or with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl; each RD and RE is independently selected from hydrogen, hydroxyl, C1-C6 alkyl, and C1- C6 alkoxy; each R3A and R3B is independently selected from hydrogen C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl, or R3A and R3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group; R4 is hydrogen, C1-C6 alkyl, or acrylamido; R5 is hydrogen, C1-C6 alkyl, cyano, -NR5AR5B, -NR5AC(=O)R5B, or -C(=O)NR5AR5B; R5A and R5B are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 hydroxyalkyl; R6 is hydrogen, halogen, or C1-C6 alkyl; X is a bond, CH2, CH(CH3), C(CH3)2, or
Figure imgf000005_0001
Z is NR3B or O; Y is phenyl optionally substituted with 1-3 independently selected RY, naphthyl optionally substituted with 1-3 independently selected RY, or 5-10 membered heteroaryl optionally substituted with 1-3 independently selected RY; each RY is independently selected from: halogen, cyano, hydroxyl, C1-C6 haloalkyl optionally substituted with hydroxyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, - NHC(=O)RC, -C(=O)NHRY1, –CO2RA, -SO2NRFRG, -NHSO2RF, –S(=O)(=NRF)RG, –SO2(C1-C6 alkyl), -C(=O)NRARB, 4-6 membered heteroaryl, heteroaralkyl, 4-6 membered heterocyclyl optionally substituted with RY1, and C1-C6 alkyl optionally substituted with –CO2RA or 4-6 membered heteroaryl optionally substituted with RY1; RY1 is hydroxyl, –SO2(C1-C6 alkyl), or C1-C6 alkyl optionally substituted with oxo; and each RF and RG is independently selected from hydrogen, phenyl, and C1-C6 alkyl optionally substituted with oxo or –NRARB. Some embodiments provide a compound of Formula (I-A):
Figure imgf000006_0001
or a pharmaceutically acceptable salt thereof, wherein: R1 is hydrogen, cyano, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted with phenyl optionally substituted with halogen; R2 is phenyl optionally substituted with 1-4 independently selected R2A, 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R2A, 4-10 membered heterocyclyl optionally substituted with 1-4 independently selected R2A, 4-10 membered cycloalkyl optionally substituted with 1-4 independently selected R2A, or C1-C6 alkoxy optionally substituted with –C(=O)NRARC; each R2A is independently selected from: (i) halogen, (ii) cyano, (iii) hydroxyl, (iv) -NRARB, (v) -C(=O)NRARB, (vi)
Figure imgf000006_0002
(vii) -NHC(=O)RC, (viii) -C(=O)NRDRE, (ix) -C(=O)ORF, (x) -SO2RF, (xi) -NHSO2RF, (xii) -SO2NRFRG, (xiii) -NHC(=O)C1-C6 alkyl optionally substituted with NRARB, (xiv) C1-C6 haloalkyl, (xv) C1-C6 hydroxyalkyl, (xvi) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl and -NRARB, (xvii) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, -C(=O)NRARB, or -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB, (xviii) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or –C(=O)C3-C6 cycloalkyl, (xix) C1-C6 alkoxy optionally substituted with -NRARB or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or –C(=O)C3-C6 cycloalkyl, and (xx) C3-C6 cycloalkyl optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl; each RA and RB is independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3- C6 cycloalkyl, C2-C6 alkenyl, and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy, or RA and RB together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C1-C6 alkyl, and –C(=O)C1-C6 alkyl; each RC is independently selected from C3-C6 cycloalkyl, -C(=O)NHRY1, or a C1-C6 alkyl optionally substituted with -NRARB or with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl; each RD and RE is independently selected from hydrogen, hydroxyl, C1-C6 alkyl, and C1- C6 alkoxy; each R3A and R3B is independently selected from hydrogen and C1-C6 alkyl, or R3A and R3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group; R4 is hydrogen, C1-C6 alkyl, or acrylamido; R5 is hydrogen, C1-C6 alkyl, cyano, -NR5AR5B, -NR5AC(=O)R5B, or -C(=O)NR5AR5B; R5A and R5B are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 hydroxyalkyl; R6 is hydrogen, halogen, or C1-C6 alkyl; X is a bond, CH2, CH(CH3), C(CH3)2, or
Figure imgf000008_0001
Y is phenyl optionally substituted with 1-3 independently selected RY, naphthyl optionally substituted with 1-3 independently selected RY, or 5-10 membered heteroaryl optionally substituted with 1-3 independently selected RY; each RY is independently selected from: halogen, cyano, hydroxyl, C1-C6 haloalkyl, C1- C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, -NHC(=O)RC, -C(=O)NHRY1, –CO2RA, -SO2NRFRG, -NHSO2RF, –S(=O)(=NRF)RG, –SO2(C1-C6 alkyl), -C(=O)NRARB, 5-6 membered heteroaryl, heteroaralkyl, and C1-C6 alkyl optionally substituted with –CO2RA or 5-6 membered heteroaryl optionally substituted with RY1; RY1 is –SO2(C1-C6 alkyl) or C1-C6 alkyl optionally substituted with oxo; and each RF and RG is independently selected from hydrogen, phenyl, and C1-C6 alkyl optionally substituted with oxo or –NRARB. Also provided herein is a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. Provided herein is a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Also provided herein is a method for treating cancer in a subject in need thereof, comprising (a) determining that the cancer is associated with a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Provided herein is a method of treating a PI3Kα-associated disease in a subject, comprising administering to a subject identified or diagnosed as having a PI3Kα-associated disease a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. This disclosure also provides a method of treating a PI3Kα-associated disease in a subject, comprising: determining that the cancer in the subject is a PI3Kα-associated disease; and administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Further provided herein is a method of treating a PI3Kα-associated cancer in a subject, comprising administering to a subject identified or diagnosed as having a PI3Kα-associated cancer a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. This disclosure also provides a method of treating a PI3Kα-associated cancer in a subject, comprising: determining that the cancer in the subject is a PI3Kα-associated cancer; and administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Provided herein is a method of treating a subject, comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein, to a subject having a clinical record that indicates that the subject has a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same. This disclosure also provides a method for inhibiting PI3Kα in a mammalian cell, comprising contacting the mammalian cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Other embodiments include those described in the Detailed Description and/or in the claims. Additional Definitions To facilitate understanding of the disclosure set forth herein, a number of additional terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well- known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications that are mentioned throughout the specification and the attached appendices are incorporated herein by reference in their entireties. The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation, for example, within experimental variability and/or statistical experimental error, and thus the number or numerical range may vary up to ±10% of the stated number or numerical range. The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated. The term "inhibit" or "inhibition of" means to reduce by a measurable amount, or to prevent entirely (e.g., 100% inhibition). The phrase "therapeutically effective amount" means an amount of compound that, when administered to a subject in need of such treatment, is sufficient to (i) treat a PI3Kα protein- associated disease, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, or (iii) delay the onset of one or more symptoms of the particular disease described herein. The term “pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. As used herein, the term “subject” refer to any animal, including mammals such as primates (e.g., humans), mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and/or exhibited at least one symptom of the disease to be treated and/or prevented. As used herein, terms “treat” or “treatment” refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. The term “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I). The term “oxo” refers to a divalent doubly bonded oxygen atom (i.e., “=O”). As used herein, oxo groups are attached to carbon atoms to form carbonyls. The term “hydroxyl” refers to an -OH radical. The term “cyano” refers to a -CN radical. The term “alkyl” refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C1-10 indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Non-limiting examples include methyl, ethyl, iso-propyl, tert-butyl, n-hexyl. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and/or other substituents as defined herein. The term “haloalkyl” refers to an alkyl, in which one or more hydrogen atoms is/are replaced with an independently selected halogen. The term “alkoxy” refers to an -O-alkyl radical (e.g., -OCH3). The term “alkoxyalkyl” refers to an –alkyl-O-alkyl radical (e.g., -CH2CH2OCH3). The term “thioalkyl” refers to an -S-alkyl radical (e.g., -SCH3) or an –alkyl-S-alkyl radical (e.g., -CH2CH2SCH3). The term “hydroxyalkyl” refers to an alkyl, in which one or more hydrogen atoms is/are replaced with hydroxyl. The term “aryl” refers to a 6-20 membered all carbon ring system wherein at least one ring in the system is aromatic (e.g., 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system). Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like. The term “cycloalkyl” as used herein refers to cyclic saturated hydrocarbon groups having, e.g., 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl may include multiple fused and/or bridged rings. Non-limiting examples of fused/bridged cycloalkyl includes: bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, and the like. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non- limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms. The term “heteroaryl”, as used herein, refers to a ring system having 5 to 20 ring atoms, such as 5, 6, 9, 10, or 14 ring atoms; wherein at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, S, Si, and B, and at least one ring in the system is aromatic (but does not have to be a ring which contains a heteroatom, e.g. tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). Heteroaryl groups can include monocyclic, bridged, fused, and spiro ring systems, so long as one ring in the system is aromatic. Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4- c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromane, 2,3- dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[b][1,4]oxathiine, isoindoline, and others. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl. For purposes of clarification, heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof, in which each ring nitrogen adjacent to a carbonyl is tertiary (i.e., all three valences are occupied by non-hydrogen substituents), such as one or more of pyridone (e.g.,
Figure imgf000012_0001
pyrimidone (e.g.,
Figure imgf000012_0002
pyridazinone (e.g.,
Figure imgf000012_0003
pyrazinone (e.g.,
Figure imgf000012_0004
and imidazolone (e.g., wherein each ring nitrogen adjacent
Figure imgf000012_0005
to a carbonyl is tertiary (i.e., the oxo group (i.e., “=O”) herein is a constituent part of the heteroaryl ring). The term “heterocyclyl” refers to a saturated or partially unsaturated ring systems with 3- 16 ring atoms (e.g., 3-8 membered monocyclic, 5-12 membered bicyclic, or 10-14 membered tricyclic ring system) having at least one heteroatom selected from O, N, S, Si, and B, wherein one or more ring atoms may be substituted by 1-3 oxo (forming, e.g., a lactam) and one or more N or S atoms may be substituted by 1-2 oxido (forming, e.g., an N-oxide, an S-oxide, or an S,S- dioxide), valence permitting. Heterocyclyl groups include monocyclic, bridged, fused, and spiro ring systems. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl, and the like. Heterocyclyl may include multiple fused and bridged rings. Non-limiting examples of fused/bridged heteorocyclyl includes: 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane, 3- azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6- azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane,
Figure imgf000013_0001
azabicyclo[3.2.1]octane, 2-oxabicyclo[1.1.0]butane, 2-oxabicyclo[2.1.0]pentane, 2- oxabicyclo[1.1.1]pentane, 3-oxabicyclo[3.1.0]hexane, 5-oxabicyclo[2.1.1]hexane, 3- oxabicyclo[3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6- oxabicyclo[3.1.1]heptane, 7-oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, 3- oxabicyclo[3.2.1]octane, and the like. Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1- azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6- azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane 2,5- diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2-oxaspiro[2.2]pentane, 4-oxaspiro[2.5]octane, 1-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, 1,7-dioxaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, 1- oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane, 3-oxa-9-azaspiro[5.5]undecane and the like. An “aralkyl” refers to an aryl group, as defined herein, connected to the remainder of the molecule via a divalent C1-C6 alkyl group, as described herein. Non-limiting examples of an aralkyl group are benzyl, ethylphenyl, methylnaphthyl, and the like. A “heteroaralkyl” refers to a heteroaryl group, as defined herein, connected to the remainder of the molecule via a divalent C1-C6 alkyl group, as described herein. Non-limiting examples of an aralkyl group are methylpyridyl, ethylpyrimidinyl, methylimidazolyl, and the like. As used herein, examples of aromatic rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like. As used herein, when a ring is described as being “partially unsaturated”, it means said ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or tirple bonds between constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like. For the avoidance of doubt, and unless otherwise specified, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, cycloalkyl, and the like described herein) containing a sufficient number of ring atoms to form bicyclic or higher order ring systems (e.g., tricyclic, polycyclic ring systems), it is understood that such rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms (e.g., [x.x.0] ring systems, in which 0 represents a zero atom bridge (e.g.,
Figure imgf000014_0001
)); (ii) a single ring atom (spiro-fused ring systems) (e.g.,
Figure imgf000014_0002
or (iii) a contiguous array of ring atoms (bridged ring systems having all bridge lengths > 0) (e.g.,
Figure imgf000014_0003
In addition, atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 13C and 14C. In addition, the compounds generically or specifically disclosed herein are intended to include all tautomeric forms. Thus, by way of example, a compound containing the moiety:
Figure imgf000015_0002
encompasses the tautomeric form containing the moiety:
Figure imgf000015_0001
. Similarly, a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms. The compounds provided herein may encompass various stereochemical forms. The compounds also encompass enantiomers (e.g., R and S isomers), diastereomers, as well as mixtures of enantiomers (e.g., R and S isomers) including racemic mixtures and mixtures of diastereomers, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds. Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry (e.g., a “flat” structure) and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound. Likewise, unless otherwise indicated, when a disclosed compound is named or depicted by a structure that specifies the stereochemistry (e.g., a structure with “wedge” and/or “dashed” bonds) and has one or more chiral centers, it is understood to represent the indicated stereoisomer of the compound. The details of one or more embodiments of this disclosure are set forth in the accompanying drawings and the description below. Other features and advantages of the present disclosure will be apparent from the description and drawings, and from the claims. DETAILED DESCRIPTION This disclosure provides compounds of Formula (I) and pharmaceutically acceptable salts thereof, that inhibit phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Kα). These compounds are useful for treating a disease in which increased PI3Kα activation contributes to the pathology, symptoms, and/or progression of the disease (e.g., cancer) in a subject. Formulae (I) Compounds Some embodiments provide a compound of Formula (I):
Figure imgf000016_0001
or a pharmaceutically acceptable salt thereof, wherein: R1 is hydrogen, cyano, C3-C6 cycloalkyl, C1-C6 alkyl optionally substituted with phenyl optionally substituted with halogen, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 alkoxyalkyl; R2 is phenyl optionally substituted with 1-4 independently selected R2A, 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R2A, 4-10 membered heterocyclyl optionally substituted with 1-4 independently selected R2A, 4-10 membered cycloalkyl optionally substituted with 1-4 independently selected R2A, C1-C6 alkoxyalkyl optionally substituted with –C(=O)NRARC, C1-C6 alkoxy optionally substituted with – C(=O)NRARC, or –O(R2B); each R2A is independently selected from: (i) halogen, (ii) cyano, (iii) hydroxyl, (iv) -NRARB, (v) -C(=O)NRARB, (vi)
Figure imgf000016_0002
(vii) -NHC(=O)RC, (viii) -C(=O)NRDRE, (ix) -C(=O)ORF, (x) -SO2RF, (xi) -NHSO2RF, (xii) -SO2NRFRG, (xiii) -NHC(=O)C1-C6 alkyl optionally substituted with NRARB, (xiv) C1-C6 haloalkyl, (xv) C1-C6 hydroxyalkyl, (xvi) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl and -NRARB, (xvii) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, -C(=O)NRARB, -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB, or C1- C6 alkyl optionally substituted with C1-C6 alkoxy or -NHC(=O)C1-C6 alkyl optionally substituted with C3-C16 cycloalkyl (xviii) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C1-C6 alkoxy, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or –C(=O)C3-C6 cycloalkyl, (xix) C1-C6 alkoxy optionally substituted with -NRARB or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or –C(=O)C3-C6 cycloalkyl, and (xx) C3-C6 cycloalkyl optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl; R2B is phenyl optionally substituted with 1-4 independently selected R2A, 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R2A, 4-10 membered heterocyclyl optionally substituted with 1-4 independently selected R2A, 4-10 membered cycloalkyl optionally substituted with 1-4 independently selected R2A; each RA and RB is independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3- C6 cycloalkyl, C2-C6 alkenyl, –SO2(C1-C6 alkyl), and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy, or RA and RB together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C1-C6 alkyl, and –C(=O)C1-C6 alkyl; each RC is independently selected from C3-C6 cycloalkyl, -C(=O)NHRY1, or a C1-C6 alkyl optionally substituted with -NRARB or with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl; each RD and RE is independently selected from hydrogen, hydroxyl, C1-C6 alkyl, and C1- C6 alkoxy; each R3A and R3B is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl, or R3A and R3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group; R4 is hydrogen, C1-C6 alkyl, or acrylamido; R5 is hydrogen, C1-C6 alkyl, cyano, -NR5AR5B, -NR5AC(=O)R5B, or -C(=O)NR5AR5B; R5A and R5B are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 hydroxyalkyl; R6 is hydrogen, halogen, or C1-C6 alkyl; X is a bond, CH2, CH(CH3), C(CH3)2, or
Figure imgf000018_0001
Z is NR3B or O; Y is phenyl optionally substituted with 1-3 independently selected RY, naphthyl optionally substituted with 1-3 independently selected RY, or 5-10 membered heteroaryl optionally substituted with 1-3 independently selected RY; each RY is independently selected from: halogen, cyano, hydroxyl, C1-C6 haloalkyl optionally substituted with hydroxyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, - NHC(=O)RC, -C(=O)NHRY1, –CO2RA, -SO2NRFRG, -NHSO2RF, –S(=O)(=NRF)RG, –SO2(C1-C6 alkyl), -C(=O)NRARB, 4-6 membered heteroaryl, heteroaralkyl, 4-6 membered heterocyclyl optionally substituted with RY1, and C1-C6 alkyl optionally substituted with –CO2RA or 4-6 membered heteroaryl optionally substituted with RY1; RY1 is –SO2(C1-C6 alkyl), hydroxyl, or C1-C6 alkyl optionally substituted with oxo; and each RF and RG is independently selected from hydrogen, phenyl, and C1-C6 alkyl optionally substituted with oxo or –NRARB. Some embodiments provide a compound of Formula (I-A):
Figure imgf000019_0001
or a pharmaceutically acceptable salt thereof, wherein: R1 is hydrogen, cyano, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted with phenyl optionally substituted with halogen; R2 is phenyl optionally substituted with 1-4 independently selected R2A, 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R2A, 4-10 membered heterocyclyl optionally substituted with 1-4 independently selected R2A, 4-10 membered cycloalkyl optionally substituted with 1-4 independently selected R2A, or C1-C6 alkoxy optionally substituted with –C(=O)NRARC; each R2A is independently selected from: (i) halogen, (ii) cyano, (iii) hydroxyl, (iv) -NRARB, (v) -C(=O)NRARB, (vi)
Figure imgf000019_0002
(vii) -NHC(=O)RC, (viii) -C(=O)NRDRE, (ix) -C(=O)ORF, (x) -SO2RF, (xi) -NHSO2RF, (xii) -SO2NRFRG, (xiii) -NHC(=O)C1-C6 alkyl optionally substituted with NRARB, (xiv) C1-C6 haloalkyl, (xv) C1-C6 hydroxyalkyl, (xvi) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl and -NRARB, (xvii) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, -C(=O)NRARB, or -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB, (xviii) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or –C(=O)C3-C6 cycloalkyl, (xix) C1-C6 alkoxy optionally substituted with -NRARB or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or –C(=O)C3-C6 cycloalkyl, and (xx) C3-C6 cycloalkyl optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl; each RA and RB is independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3- C6 cycloalkyl, C2-C6 alkenyl, and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy, or RA and RB together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C1-C6 alkyl, and –C(=O)C1-C6 alkyl; each RC is independently selected from C3-C6 cycloalkyl, -C(=O)NHRY1, or a C1-C6 alkyl optionally substituted with -NRARB or with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl; each RD and RE is independently selected from hydrogen, hydroxyl, C1-C6 alkyl, and C1- C6 alkoxy; each R3A and R3B is independently selected from hydrogen and C1-C6 alkyl, or R3A and R3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group; R4 is hydrogen, C1-C6 alkyl, or acrylamido; R5 is hydrogen, C1-C6 alkyl, cyano, -NR5AR5B, -NR5AC(=O)R5B, or -C(=O)NR5AR5B; R5A and R5B are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 hydroxyalkyl; R6 is hydrogen, halogen, or C1-C6 alkyl; X is a bond, CH2, CH(CH3), C(CH3)2, or
Figure imgf000021_0001
Y is phenyl optionally substituted with 1-3 independently selected RY, naphthyl optionally substituted with 1-3 independently selected RY, or 5-10 membered heteroaryl optionally substituted with 1-3 independently selected RY; each RY is independently selected from: halogen, cyano, hydroxyl, C1-C6 haloalkyl, C1- C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, -NHC(=O)RC, -C(=O)NHRY1, –CO2RA, -SO2NRFRG, -NHSO2RF, –S(=O)(=NRF)RG, –SO2(C1-C6 alkyl), -C(=O)NRARB, 5-6 membered heteroaryl, heteroaralkyl, and C1-C6 alkyl optionally substituted with –CO2RA or 5-6 membered heteroaryl optionally substituted with RY1; RY1 is –SO2(C1-C6 alkyl) or C1-C6 alkyl optionally substituted with oxo; and each RF and RG is independently selected from hydrogen, phenyl, and C1-C6 alkyl optionally substituted with oxo or –NRARB. In some embodiments, R1 is hydrogen. In some embodiments, R1 is cyano. In some embodiments, R1 is C3-C6 cycloalkyl. In some embodiments, R1 is cyclopropyl or cyclobutyl. In some embodiments, R1 is C1-C6 alkyl optionally substituted with phenyl optionally substituted with halogen. In some embodiments, R1 is C1-C6 alkyl substituted with phenyl optionally substituted with halogen. In some embodiments, R1 is C1-C6 alkyl substituted with phenyl substituted with halogen. In some embodiments, R1 is para-fluorobenzyl. In some embodiments, R1 is C1-C6 alkyl substituted with phenyl. In some embodiments, R1 is benzyl. In some embodiments, R1 is ethyl-1-phenyl or ethyl-2-phenyl. In some embodiments, R1 is C1- C6 alkyl. In some embodiments, R1 is methyl, ethyl, or isopropyl. In some embodiments, R1 is methyl. In some embodiments, R1 is C1-C6 thioalkyl. In some embodiments, R1 is C1-C3 thioalkyl. In some embodiments, R1 is thiomethyl, thioethyl, or thiopropyl. In some embodiments, R1 is methyl-thiomethyl, methyl-thioethyl, or ethyl-thiomethyl. In some embodiments, R1 is thiomethyl. In some embodiments, R1 is C1-C6 haloalkyl. In some embodiments, R1 is C1-C3 haloalkyl. In some embodiments, R1 is C1-C3 fluoroalkyl. In some embodiments, R1 is CF3. In some embodiments, R1 is CHF2. In some embodiments, R1 is C1-C6 alkoxy. In some embodiments, R1 is C1-C3 alkoxy. In some embodiments, R1 is –OCH3, –OCH2CH3, or –OCH2CH2CH3. In some embodiments, R1 is –OCH3. In some embodiments, R1 is C1-C6 alkoxyalkyl. In some embodiments, R1 is C1-C3 alkoxyalkyl. In some embodiments, R1 is –CH2OCH3, –CH2OCH2CH3, or –CH2CH2OCH3. In some embodiments, R1 is –CH2OCH3. In some embodiments, R2 is phenyl optionally substituted with 1-4 independently selected R2A. In some embodiments, R2 is phenyl substituted with 1 or 2 independently selected R2A. In some embodiments, R2 is phenyl substituted with 1 R2A. In some embodiments, R2 is phenyl substituted with 2 independently selected R2A. In some embodiments, R2 is phenyl optionally substituted with 3 independently selected R2A. In some embodiments, R2 is phenyl. In some embodiments, R2 is 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R2A. In some embodiments, R2 is 5-10 membered heteroaryl substituted with 1 or 2 independently selected R2A. In some embodiments, R2 is 5-10 membered heteroaryl substituted with 1 R2A. In some embodiments, R2 is 5-10 membered heteroaryl substituted with 2 independently selected R2A. In some embodiments, R2 is 5-10 membered heteroaryl optionally substituted with 3 independently selected R2A. In some embodiments, R2 is 5-10 membered heteroaryl. In some embodiments, R2 is 6 membered heteroaryl optionally substituted with 1-4 independently selected R2A. In some embodiments, R2 is 6 membered heteroaryl substituted with 1 or 2 independently selected R2A. In some embodiments, R2 is 6 membered heteroaryl substituted with 1 R2A. In some embodiments, R2 is 6 membered heteroaryl substituted with 2 independently selected R2A. In some embodiments, R2 is 6 membered heteroaryl optionally substituted with 3 independently selected R2A. In some embodiments, R2 is 6 membered heteroaryl. In some embodiments, R2 is 9 membered heteroaryl optionally substituted with 1-4 independently selected R2A. In some embodiments, R2 is 9 membered heteroaryl substituted with 1 or 2 independently selected R2A. In some embodiments, R2 is 9 membered heteroaryl substituted with 1 R2A. In some embodiments, R2 is 9 membered heteroaryl substituted with 2 independently selected R2A. In some embodiments, R2 is 9 membered heteroaryl optionally substituted with 3 independently selected R2A. In some embodiments, R2 is 9 membered heteroaryl. In some embodiments, the heteroaryl of R2 is pyridinyl, pyrimidinyl, pyridazinyl, indole, indazole, azaindole, azaindazole, indoline, azaindoline, isoindoline, azaisoindoline, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzoisoxazolyl, benzisothiazolyl, quinolinyl, or isoquinolinyl. In some embodiments, the heteroaryl of R2 is pyridinyl or pyrimidinyl. In some embodiments, the heteroaryl of R2 is indole, indazole, azaindole, azaindazole, indoline, azaindoline, isoindoline, or azaisoindoline. In some embodiments, R2 is 4-10 membered heterocyclyl optionally substituted with 1-4 independently selected R2A. In some embodiments, R2 is 4-10 membered heterocyclyl substituted with 1 or 2 independently selected R2A. In some embodiments, R2 is 4-10 membered heterocyclyl substituted with 1 R2A. In some embodiments, R2 is 4-10 membered heterocyclyl substituted with 2 independently selected R2A. In some embodiments, R2 is 4-10 membered heterocyclyl optionally substituted with 3 independently selected R2A. In some embodiments, R2 is 4-10 membered heterocyclyl. In some embodiments, R2 is 5-8 membered heterocyclyl optionally substituted with 1-4 independently selected R2A. In some embodiments, R2 is 5-8 membered heterocyclyl substituted with 1 or 2 independently selected R2A. In some embodiments, R2 is 5-8 membered heterocyclyl substituted with 1 R2A. In some embodiments, R2 is 5-8 membered heterocyclyl substituted with 2 independently selected R2A. In some embodiments, R2 is 5-8 membered heterocyclyl optionally substituted with 3 independently selected R2A. In some embodiments, R2 is 5-8 membered heterocyclyl. In some embodiments, the heterocyclyl of R2 is piperidinyl, piperazinyl, or morpholinyl. In some embodiments, R2 is 4-10 membered cycloalkyl optionally substituted with 1-4 independently selected R2A. In some embodiments, R2 is 4-10 membered cycloalkyl substituted with 1 or 2 independently selected R2A. In some embodiments, R2 is 4-10 membered cycloalkyl substituted with 1 R2A. In some embodiments, R2 is 4-10 membered cycloalkyl substituted with 2 independently selected R2A. In some embodiments, R2 is 4-10 membered cycloalkyl optionally substituted with 3 independently selected R2A. In some embodiments, R2 is 4-10 membered cycloalkyl. In some embodiments, R2 is 5-7 membered cycloalkyl optionally substituted with 1-4 independently selected R2A. In some embodiments, R2 is 5-7 membered cycloalkyl substituted with 1 or 2 independently selected R2A. In some embodiments, R2 is 5-7 membered cycloalkyl substituted with 1 R2A. In some embodiments, R2 is 5-7 membered cycloalkyl substituted with 2 independently selected R2A. In some embodiments, R2 is 5-7 membered cycloalkyl optionally substituted with 3 independently selected R2A. In some embodiments, R2 is 5-7 membered cycloalkyl. In some embodiments, the cycloalkyl of R2 is cyclopentyl, [1.1.1]bicyclopentyl, or cyclohexyl. In some embodiments, R2 is C1-C6 alkoxyalkyl optionally substituted with –C(=O)NRARC. In some embodiments, R2 is C1-C6 alkoxyalkyl. In some embodiments, R2 is C1-C3 alkoxyalkyl. In some embodiments, R2 is –CH2OCH3, –CH2OCH2CH3, or – CH2CH2OCH3. In some embodiments, R2 is –CH2OCH3. In some embodiments, 1, 2, 3, or 4 of R2A are independently halogen. In some embodiments, 1, 2, or 3 of R2A are independently fluoro or chloro. In some embodiments, 1 or 2 of R2A are independently fluoro or chloro. In some embodiments, 1, 2, 3, or 4 of R2A are independently cyano. In some embodiments, 1 or 2 of R2A are cyano. In some embodiments, 1, 2, 3, or 4 of R2A are independently hydroxyl. In some embodiments, 1 or 2 of R2A are hydroxyl. In some embodiments, 1, 2, 3, or 4 of R2A are independently -NRARB. In some embodiments, 1 or 2 of R2A are independently -NRARB. In some embodiments, 1, 2, 3, or 4 of R2A are independently -C(=O)NRARB. In some embodiments, 1 or 2 of R2A are independently -C(=O)NRARB. In some embodiments, 1, 2, 3, or 4 of R2A are independently
Figure imgf000024_0001
In some embodiments, 1 or 2 of R2A are independently
Figure imgf000024_0002
In some embodiments, 1, 2, 3, or 4 of R2A are independently -NHC(=O)RC. In some embodiments, 1 or 2 of R2A are independently -NHC(=O)RC. In some embodiments, 1, 2, 3, or 4 of R2A are independently -C(=O)NRDRE. In some embodiments, 1 or 2 of R2A are independently -C(=O)NRDRE. In some embodiments, 1, 2, 3, or 4 of R2A are independently -C(=O)ORF. In some embodiments, 1 or 2 of R2A are independently -C(=O)ORF. In some embodiments, 1, 2, 3, or 4 of R2A are independently -SO2RF. In some embodiments, 1 or 2 of R2A are independently -SO2RF. In some embodiments, 1, 2, 3, or 4 of R2A are independently -NHSO2RF. In some embodiments, 1 or 2 of R2A are independently -NHSO2RF. In some embodiments, 1, 2, 3, or 4 of R2A are independently -SO2NRFRG. In some embodiments, 1 or 2 of R2A are independently -SO2NRFRG. In some embodiments, 1, 2, 3, or 4 of R2A are independently -NHC(=O)C1-C6 alkyl optionally substituted with NRARB. In some embodiments, 1, 2, or 3 of R2A are independently -NHC(=O)C1-C6 alkyl substituted with NRARB. In some embodiments, 1, 2, or 3 of R2A are independently -NHC(=O)C1-C6 alkyl. In some embodiments, 1 or 2 of R2A are independently -NHC(=O)C1-C6 alkyl optionally substituted with NRARB. In some embodiments, 1 or 2 of R2A are independently -NHC(=O)C1-C6 alkyl substituted with NRARB. In some embodiments, 1 or 2 of R2A are independently -NHC(=O)C1-C6 alkyl. In some embodiments, 1, 2, 3, or 4 of R2A are independently C1-C6 haloalkyl. In some embodiments, 1 or 2 of R2A are independently C1-C3 haloalkyl. In some embodiments, 1 or 2 of R2A are trifluoromethyl. In some embodiments, 1, 2, 3, or 4 of R2A are independently C1-C6 hydroxyalkyl. In some embodiments, 1 or 2 of R2A are independently C1-C3 hydroxyalkyl. In some embodiments, 1, 2, 3, or 4 of R2A are independently 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl and - NRARB. In some embodiments, 1, 2, 3, or 4 of R2A are independently 5-10 membered heteroaryl substituted with 1-3 substituents independently selected from C1-C6 alkyl and -NRARB. In some embodiments, 1, 2, 3, or 4 of R2A are independently 5-10 membered heteroaryl. In some embodiments, 1 of R2A is 5-6 membered heteroaryl optionally substituted with 1- 3 substituents independently selected from C1-C6 alkyl and -NRARB. In some embodiments, 1 of R2A is 5-6 membered heteroaryl substituted with 1-3 substituents independently selected from C1-C6 alkyl and -NRARB. In some embodiments, 1 of R2A is 5-6 membered heteroaryl. In some embodiments, 1, 2, 3, or 4 of R2A are independently 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, -C(=O)NRARB, -NHC(=O)C1- C6 alkyl optionally substituted with -NRARB, or C1-C6 alkyl optionally substituted with C1-C6 alkoxy or -NHC(=O)C1-C6 alkyl optionally substituted with C3-C16 cycloalkyl. In some embodiments, 1 of R2A is 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, - SO2(C1-C6 alkyl), -SO2NRFRG, -C(=O)NRARB, -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB, or C1-C6 alkyl optionally substituted with C1-C6 alkoxy or -NHC(=O)C1-C6 alkyl optionally substituted with C3-C16 cycloalkyl.. In some embodiments, 1, 2, 3, or 4 of R2A are independently 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, - C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, -C(=O)NRARB, -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB, or C1-C6 alkyl optionally substituted with C1-C6 alkoxy or -NHC(=O)C1-C6 alkyl optionally substituted with C3-C16 cycloalkyl. In some embodiments, 1 of R2A is 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, - C(=O)NRARB, -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB, or C1-C6 alkyl optionally substituted with C1-C6 alkoxy or -NHC(=O)C1-C6 alkyl optionally substituted with C3-C16 cycloalkyl. In some embodiments, 1, 2, 3, or 4 of R2A are independently 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, C1-C6 alkyl substituted with C1-C6 alkoxy, -C(=O)NRARB, or -NHC(=O)C1-C6 alkyl substituted with -NRARB. In some embodiments, 1 of R2A is 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, C1-C6 alkyl substituted with C1-C6 alkoxy, -C(=O)NRARB, or -NHC(=O)C1-C6 alkyl substituted with -NRARB. In some embodiments, 1, 2, 3, or 4 of R2A are independently 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, C1-C6 alkyl, -C(=O)NRARB, or -NHC(=O)C1-C6 alkyl. In some embodiments, 1 of R2A is 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, C1-C6 alkyl, -C(=O)NRARB, or -NHC(=O)C1-C6 alkyl. In some embodiments, 1, 2, 3, or 4 of R2A are independently 4-10 membered heterocyclyl substituted with C1-C6 alkyl optionally substituted with C1-C6 alkoxy or -NHC(=O)C1-C6 alkyl optionally substituted with C3-C16 cycloalkyl. In some embodiments, R2A is C1-C6 alkyl substituted with C1-C6 alkoxy or -NHC(=O)C1-C6 alkyl optionally substituted with C3-C16 cycloalkyl. In some embodiments, 1, 2, 3, or 4 of R2A are independently 4-10 membered heterocyclyl. In some embodiments, 1 of R2A is 4-10 membered heterocyclyl. In some embodiments, 1, 2, or 3 of R2A are independently C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or –C(=O)C3-C6 cycloalkyl. In some embodiments, 1, 2, 3, or 4 of R2A are independently C1-C6 alkyl substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or –C(=O)C3-C6 cycloalkyl. In some embodiments, 1, 2, 3, or 4 of R2A are independently C1-C6 alkyl substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, and 4-10 membered heterocyclyl substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or –C(=O)C3-C6 cycloalkyl. In some embodiments, 1, 2, 3, or 4 of R2A are independently C1-C6 alkyl substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, and 4-10 membered heterocyclyl. In some embodiments, 1, 2, 3, or 4 of R2A are independently C1-C6 alkyl. In some embodiments, 1, 2, or 3 of R2A are independently C1-C3 alkyl. In some embodiments, 1, 2, or 3 of R2A are methyl. In some embodiments, 1 or 2 of R2A are independently C1-C6 alkyl. In some embodiments, 1 or 2 of R2A are independently C1-C3 alkyl. In some embodiments, 1 or 2 of R2A are methyl. In some embodiments, 1, 2, 3, or 4 of R2A are independently C1-C6 alkoxy optionally substituted with -NRARB or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or –C(=O)C3-C6 cycloalkyl. In some embodiments, 1, 2, 3, or 4 of R2A are independently C1-C6 alkoxy substituted with -NRARB or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or –C(=O)C3-C6 cycloalkyl. In some embodiments, 1, 2, 3, or 4 of R2A are independently C1-C6 alkoxy substituted with -NRARB or 4-10 membered heterocyclyl substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or –C(=O)C3-C6 cycloalkyl. In some embodiments, 1, 2, 3, or 4 of R2A are independently C1-C6 alkoxy substituted with -NRARB or 4-10 membered heterocyclyl. In some embodiments, 1, 2, 3, or 4 of R2A are independently C1-C6 alkoxy. In some embodiments, 1, 2, 3, or 4 of R2A are independently C3-C6 cycloalkyl optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, 1, 2, 3, or 4 of R2A are independently C3-C6 cycloalkyl substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, 1, 2, 3, or 4 of R2A are independently C3-C6 cycloalkyl substituted with 4-10 membered heterocyclyl substituted with C1-C6 alkyl. In some embodiments, 1, 2, 3, or 4 of R2A are independently C3-C6 cycloalkyl substituted with 4-10 membered heterocyclyl. In some embodiments, 1, 2, 3, or 4 of R2A are independently C3-C6 cycloalkyl. In some embodiments, 1 or 2 of R2A are independently C3-C6 cycloalkyl. In some embodiments, R2 is –O(R2B). In some embodiments, R2B is phenyl optionally substituted with 1-4 independently selected R2A. In some embodiments, R2B is phenyl substituted with 1 or 2 independently selected R2A. In some embodiments, R2B is phenyl substituted with 1 R2A. In some embodiments, R2B is phenyl substituted with 2 independently selected R2A. In some embodiments, R2B is phenyl optionally substituted with 3 independently selected R2A. In some embodiments, R2B is phenyl. In some embodiments, R2B is 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R2A. In some embodiments, R2B is 5-10 membered heteroaryl substituted with 1 or 2 independently selected R2A. In some embodiments, R2B is 5-10 membered heteroaryl substituted with 1 R2A. In some embodiments, R2B is 5-10 membered heteroaryl substituted with 2 independently selected R2A. In some embodiments, R2B is 5-10 membered heteroaryl optionally substituted with 3 independently selected R2A. In some embodiments, R2B is 5-10 membered heteroaryl. In some embodiments, the heteroaryl of R2B is pyridinyl, pyrimidinyl, pyridazinyl, indole, indazole, azaindole, azaindazole, indoline, azaindoline, isoindoline, azaisoindoline, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzoisoxazolyl, benzisothiazolyl, quinolinyl, or isoquinolinyl. In some embodiments, the heteroaryl of R2B is pyridinyl or pyrimidinyl. In some embodiments, the heteroaryl of R2B is indole, indazole, azaindole, azaindazole, indoline, azaindoline, isoindoline, or azaisoindoline. In some embodiments, R2B is 4-10 membered heterocyclyl optionally substituted with 1-4 independently selected R2A. In some embodiments, R2B is 4-10 membered heterocyclyl substituted with 1 or 2 independently selected R2A. In some embodiments, R2B is 4-10 membered heterocyclyl substituted with 1 R2A. In some embodiments, R2B is 4-10 membered heterocyclyl substituted with 2 independently selected R2A. In some embodiments, R2B is 4-10 membered heterocyclyl optionally substituted with 3 independently selected R2A. In some embodiments, R2B is 4-10 membered heterocyclyl. In some embodiments, R2B is 5-8 membered heterocyclyl optionally substituted with 1-4 independently selected R2A. In some embodiments, R2B is 5-8 membered heterocyclyl substituted with 1 or 2 independently selected R2A. In some embodiments, R2B is 5-8 membered heterocyclyl substituted with 1 R2A. In some embodiments, R2B is 5-8 membered heterocyclyl substituted with 2 independently selected R2A. In some embodiments, R2B is 5-8 membered heterocyclyl optionally substituted with 3 independently selected R2A. In some embodiments, R2B is 5-8 membered heterocyclyl. In some embodiments, the heterocyclyl of R2B is piperidinyl, piperazinyl, tetrahydropyranyl, or morpholinyl. In some embodiments, R2B is 4-10 membered cycloalkyl optionally substituted with 1-4 independently selected R2A. In some embodiments, R2B is 4-10 membered cycloalkyl substituted with 1 or 2 independently selected R2A. In some embodiments, R2B is 4-10 membered cycloalkyl substituted with 1 R2A. In some embodiments, R2B is 4-10 membered cycloalkyl substituted with 2 independently selected R2A. In some embodiments, R2B is 4-10 membered cycloalkyl optionally substituted with 3 independently selected R2A. In some embodiments, R2B is 4-10 membered cycloalkyl. In some embodiments, the cycloalkyl of R2B is cyclopentyl, [1.1.1]bicyclopentyl, or cyclohexyl. In some embodiments, R2 is piperidinyl substituted with 1-2 independently selected R2A. In some embodiments, R2 is piperidinyl substituted with 2-4 independently selected R2A. In some embodiments, R2 is morpholinyl substituted with 2-4 independently selected R2A. In some embodiments, R2 is morpholinyl. In some embodiments, R2 is piperazinyl substituted with 1-2 independently selected R2A. In some embodiments, R2 is phenyl substituted with 1-2 independently selected R2A. In some embodiments, R2 is indolyl substituted with 1-2 independently selected R2A. In some embodiments, R2 is indolyl substituted with 2 independently selected R2A, where at least one R2A is C1-C6 alkyl. In some embodiments, R2 is indolyl substituted with 2 independently selected R2A, where one R2A is C1-C6 alkyl and one R2A is 4-10 membered heterocyclyl. In some embodiments, R2 is indazolyl substituted with 1-2 independently selected R2A. In some embodiments, R2 is 7-azaindolyl substituted with 1-2 independently selected R2A. In some embodiments, R2 is 7-azaindazolyl substituted with 1-2 independently selected R2A. In some embodiments, R2 is 1,2-dihydro-3H-indazol-3-one substituted with 1-2 independently selected R2A. In some embodiments, R2 is isoindolinyl substituted with 1-2 independently selected R2A. In some embodiments, R2 is isoindolinyl. In some embodiments, R2 is 2- indolinone substituted with 1-2 independently selected R2A. In some embodiments, R2 is beznimidazolyl substituted with 1-2 independently selected R2A. In some embodiments, R2 is imidazopyridinyl substituted with 1-2 independently selected R2A. In some embodiments, R2 is 1,3-dihydro-2H-benzo[d]imidazol-2-onyl substituted with 1-2 independently selected R2A. In some embodiments, R2 is [1,2,4]triazolo[1,5-a]pyridine substituted with 1-2 independently selected R2A. In some embodiments, one R2A is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, or hydroxyl, and the other R2A are independently selected from C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, hydroxyl, halogen, -NRARB, -C(=O)NRARB,
Figure imgf000031_0001
- NHC(=O)RC, -C(=O)NRDRE, -C(=O)ORF, -SO2RF, -NHSO2RF, -SO2NRFRG, -NHC(=O)C1-C6 alkyl optionally substituted with NRARB, 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl and -NRARB, 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, -C(=O)NRARB, or -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB, C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C1-C6 alkoxy, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or –C(=O)C3-C6 cycloalkyl, C1-C6 alkoxy optionally substituted with -NRARB or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or –C(=O)C3-C6 cycloalkyl, and C3-C6 cycloalkyl optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, each R2A is independently selected from halogen, methyl, ethyl, -NH2, -NHCH3, -N(CH3)2, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)NHOH, -SO2NH2, -SO2NHCH3, -SO2N(CH3)2, cyclopropyl, cyclobutyl, trifluoromethyl, 2,2,2- trifluoroethyl, and acetyl. In some embodiments, 1, 2, or 3 R2A are independently selected from halogen, methyl, ethyl, -NH2, -NHCH3, -N(CH3)2, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)NHOH, -SO2NH2, -SO2NHCH3, -SO2N(CH3)2, cyclopropyl, cyclobutyl, trifluoromethyl, 2,2,2- trifluoroethyl, and acetyl. In some embodiments, 1 or 2 R2A are independently selected from halogen, methyl, ethyl, -NH2, -NHCH3, -N(CH3)2, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)NHOH, -SO2NH2, -SO2NHCH3, -SO2N(CH3)2, cyclopropyl, cyclobutyl, trifluoromethyl, 2,2,2- trifluoroethyl, and acetyl. In some embodiments, R2 is substituted with 1 R2A. In some embodiments, R2 is substituted with 2 independently selected R2A. In some embodiments, R2 is substituted with 3 independently selected R2A. In some embodiments, R2 is substituted with 4 independently selected R2A. In some embodiments, R2 is substituted with 1 R2A. In some embodiments, R2A is halogen. In some embodiments, R2A is fluoro or chloro.. In some embodiments, R2A is cyano. In some embodiments, R2A is hydroxyl. In some embodiments, R2A is R2A -NRARB. In some embodiments, R2A is -C(=O)NRARB. In some embodiments, R2A is
Figure imgf000032_0001
In some embodiments, R2A is -NHC(=O)RC. In some embodiments, -C(=O)NRDRE. In some embodiments, R2A is -C(=O)ORF. In some embodiments, R2A is -SO2RF. In some embodiments, R2A is -NHSO2RF. In some embodiments, R2A is -NHC(=O)C1-C6 alkyl optionally substituted with NRARB. In some embodiments, R2A is C1-C6 haloalkyl. In some embodiments, R2A is C1- C6 hydroxyalkyl. In some embodiments, R2A is 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl and -NRARB. In some embodiments, R2A is 5-6 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl and -NRARB. In some embodiments, R2A is 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, -C(=O)NRARB, or -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB. In some embodiments, R2A is 4-10 membered heterocyclyl. In some embodiments, R2A is C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C1-C6 alkoxy, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or –C(=O)C3-C6 cycloalkyl. In some embodiments, R2A is C1-C6 alkyl. In some embodiments, R2A is C1-C6 alkoxy optionally substituted with -NRARB or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or –C(=O)C3-C6 cycloalkyl. In some embodiments, R2A is C1-C6 alkoxy. In some embodiments, R2A is C3-C6 cycloalkyl optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, R2A is selected from halogen, methyl, ethyl, -NH2, -NHCH3, -N(CH3)2, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)NHOH, -SO2NH2, -SO2NHCH3, -SO2N(CH3)2, cyclopropyl, cyclobutyl, trifluoromethyl, 2,2,2- trifluoroethyl, and acetyl. In some embodiments, R2 is C1-C6 alkoxy optionally substituted with –C(=O)NRARC. In some embodiments, R2 is C1-C6 alkoxy substituted with –C(=O)NRARC. In some embodiments, R2 is C3-C6 alkoxy substituted with –C(=O)NRARC. In some embodiments, R2 is C1-C6 alkoxy. In some embodiments, R2 is C1-C6 alkylalkoxy optionally substituted with – C(=O)NRARC. In some embodiments, R2 is C1-C6 alkylalkoxy substituted with –C(=O)NRARC. In some embodiments, R2 is C3-C6 alkylalkoxy substituted with –C(=O)NRARC. In some embodiments, R2 is C1-C6 alkylalkoxy. In some embodiments, X is a bond. In some embodiments, X is CH2. In some embodiments, X is CH(CH3). In some embodiments, X is C(CH3)2. In some embodiments, X is
Figure imgf000033_0001
In some embodiments, Z is O. In some embodiments, R3A is hydrogen. In some embodiments, R3A is C1-C6 alkyl. In some embodiments, R3A is methyl or ethyl. In some embodiments, R3A is methyl. In some embodiments, R3A is C1-C6 alkoxy. In some embodiments, R3A is C1-C3 alkoxy. In some embodiments, R3A is –OCH3, -OCH2CH3, or –OCH2CH2CH3. In some embodiments, R3A is –OCH3. In some embodiments, R3A is C1-C6 haloalkyl. In some embodiments, R3A is C1-C3 haloalkyl. In some embodiments, R3A is C1-C3 fluoroalkyl. In some embodiments, R3A is CF3. In some embodiments, R3A is CHF2. In some embodiments, Z is NR3B. In some embodiments, one of R3A and R3B is hydrogen and the other of R3A and R3B is C1-C6 alkyl. In some embodiments, one of R3A and R3B is hydrogen and the other of R3A and R3B is methyl. In some embodiments, each of R3A and R3B is hydrogen. In some embodiments, each of R3A and R3B is an independently selected C1-C6 alkyl. In some embodiments, each of R3A and R3B is methyl. In some embodiments, one of R3A and R3B is hydrogen and the other of R3A and R3B is C1-C6 alkoxy. In some embodiments, one of R3A and R3B is C1-C6 alkyl and the other of R3A and R3B is C1-C6 alkoxy. In some embodiments, R3A is C1-C6 alkoxy. In some embodiments, R3A is C1-C3 alkoxy. In some embodiments, R3A is –OCH3, -OCH2CH3, or –OCH2CH2CH3. In some embodiments, R3A is –OCH3. In some embodiments, one of R3A and R3B is hydrogen and the other of R3A and R3B is C1-C6 haloalkyl. In some embodiments, one of R3A and R3B is C1-C6 alkyl and the other of R3A and R3B is C1-C6 haloalkyl. In some embodiments, R3A is C1-C6 haloalkyl. In some embodiments, R3A is C1-C3 haloalkyl. In some embodiments, R3A is C1-C3 fluoroalkyl. In some embodiments, R3A is CF3. In some embodiments, R3A is CHF2. In some embodiments, R3A and R3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group. In some embodiments, R3A and R3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 5-6 membered heterocyclyl group. In some embodiments, Y is phenyl optionally substituted with RY, naphthyl substituted with RY, or 5-10 membered heteroaryl substituted with RY. In some embodiments, Y is phenyl optionally substituted with 1-3 independently selected RY. In some embodiments, Y is phenyl substituted with 1 or 2 independently selected RY. In some embodiments, Y is phenyl substituted with 1 RY. In some embodiments, Y is phenyl substituted with 2 independently selected RY. In some embodiments, Y is phenyl optionally substituted with 3 independently selected RY. In some embodiments, Y is phenyl. In some embodiments, Y is naphthyl optionally substituted with 1-3 independently selected RY. In some embodiments, Y is naphthyl substituted with 1 or 2 independently selected RY. In some embodiments, Y is naphthyl substituted with 1 RY. In some embodiments, Y is naphthyl substituted with 2 independently selected RY. In some embodiments, Y is naphthyl optionally substituted with 3 independently selected RY. In some embodiments, Y is naphthyl. In some embodiments, Y is 5-10 membered heteroaryl optionally substituted with 1-3 independently selected RY. In some embodiments, Y is 5-10 membered heteroaryl substituted with 1 or 2 independently selected RY. In some embodiments, Y is 5-10 membered heteroaryl substituted with 1 RY. In some embodiments, Y is 5-10 membered heteroaryl substituted with 2 independently selected RY. In some embodiments, Y is 5-10 membered heteroaryl optionally substituted with 3 independently selected RY. In some embodiments, Y is 5-10 membered heteroaryl. In some embodiments, Y is 6 membered heteroaryl optionally substituted with 1-3 independently selected RY. In some embodiments, Y is 6 membered heteroaryl substituted with 1 or 2 independently selected RY. In some embodiments, Y is 6 membered heteroaryl substituted with 1 RY. In some embodiments, Y is 6 membered heteroaryl substituted with 2 independently selected RY. In some embodiments, Y is 6 membered heteroaryl optionally substituted with 3 independently selected RY. In some embodiments, Y is 6 membered heteroaryl. In some embodiments, Y is 9 membered heteroaryl optionally substituted with 1-3 independently selected RY. In some embodiments, Y is 9 membered heteroaryl substituted with 1 or 2 independently selected RY. In some embodiments, Y is 9 membered heteroaryl substituted with 1 RY. In some embodiments, Y is 9 membered heteroaryl substituted with 2 independently selected RY. In some embodiments, Y is 9 membered heteroaryl optionally substituted with 3 independently selected RY. In some embodiments, Y is 9 membered heteroaryl. In some embodiments, 1, 2, or 3 of RY is independently halogen. In some embodiments, 1, 2, or 3 of RY is independently chloro or fluoro. In some embodiments, 1 or 2 of RY is independently chloro or fluoro. In some embodiments, 1, 2, or 3 of RY is hydroxyl. In some embodiments, 1 or 2 of RY is hydroxyl. In some embodiments, 1, 2, or 3 of RY is cyano. In some embodiments, 1 or 2 of RY is cyano. In some embodiments, 1, 2, or 3 of RY is independently C1-C6 haloalkyl optionally substituted with hydroxyl. In some embodiments, 1, 2, or 3 of RY is independently C1-C6 haloalkyl substituted with hydroxyl. In some embodiments, 1, 2, or 3 of RY is independently C1- C6 haloalkyl. In some embodiments, 1 or 2 of RY is independently C1-C3 haloalkyl. In some embodiments, 1 or 2 of RY is trifluoromethyl. In some embodiments, 1, 2, or 3 of RY is independently C1-C6 alkoxy. In some embodiments, 1 or 2 of RY is independently C1-C3 alkoxy. In some embodiments, 1 or 2 of RY is methoxy. In some embodiments, 1, 2, or 3 of RY is independently C1-C6 haloalkoxy. In some embodiments, 1 or 2 of RY is independently C1-C3 haloalkoxy. In some embodiments, 1 or 2 of RY is trifluoromethoxy. In some embodiments, 1, 2, or 3 of RY is independently C1-C6 hydroxyalkyl. In some embodiments, 1 or 2 of RY is independently C1-C3 hydroxyalkyl. In some embodiments, 1 or 2 of RY is independently mono-hydroxyl C1-C3 alkyl. In some embodiments, 1 or 2 of RY is independently di-hydroxyl C2-C3 alkyl. In some embodiments, 1, 2, or 3 of RY is independently -NHC(=O)RC. In some embodiments, 1 or 2 of RY is independently -NHC(=O)RC. In some embodiments, 1 of RY is -NHC(=O)RC. In some embodiments, Y is substituted with 1 RY, and RY is -NHC(=O)RC. In some embodiments, 1, 2, or 3 of RY is independently -C(=O)NHRY1. In some embodiments, 1 or 2 of RY is independently -C(=O)NHRY1. In some embodiments, 1 of RY is -C(=O)NHRY1. In some embodiments, Y is substituted with 1 RY, and RY is -C(=O)NHRY1. In some embodiments, 1, 2, or 3 of RY is independently –CO2RA. In some embodiments, 1 or 2 of RY is independently –CO2RA. In some embodiments, 1 of RY is –CO2RA. In some embodiments, Y is substituted with 1 RY, and RY is –CO2RA. In some embodiments, Y is substituted with 1 RY, and RY is –CO2H. In some embodiments, 1, 2, or 3 of RY is independently -SO2NRFRG. In some embodiments, 1 or 2 of RY is independently -SO2NRFRG. In some embodiments, 1 of RY is -SO2NRFRG. In some embodiments, Y is substituted with 1 RY, and RY is -SO2NRFRG. In some embodiments, 1, 2, or 3 of RY is independently -NHSO2RF. In some embodiments, 1 or 2 of RY is independently -NHSO2RF. In some embodiments, 1 of RY is - NHSO2RF. In some embodiments, Y is substituted with 1 RY, and RY is -NHSO2RF. In some embodiments, 1, 2, or 3 of RY is independently –S(=O)(=NRF)RG. In some embodiments, 1 or 2 of RY is independently –S(=O)(=NRF)RG. In some embodiments, 1 of RY is –S(=O)(=NRF)RG. In some embodiments, Y is substituted with 1 RY, and RY is – S(=O)(=NRF)RG. In some embodiments, 1, 2, or 3 of RY is independently –SO2(C1-C6 alkyl). In some embodiments, 1 or 2 of RY is independently –SO2(C1-C6 alkyl). In some embodiments, 1 of RY is –SO2(C1-C6 alkyl). In some embodiments, 1 or 2 of RY is –SO2CH3. In some embodiments, 1 of RY is –SO2CH3. In some embodiments, Y is substituted with 1 RY, and RY is –SO2CH3. In some embodiments, 1, 2, or 3 of RY is independently -C(=O)NRARB. In some embodiments, 1 or 2 of RY is independently -C(=O)NRARB. In some embodiments, 1 of RY is -C(=O)NRARB. In some embodiments, Y is substituted with 1 RY, and RY is -C(=O)NRARB. In some embodiments, 1, 2, or 3 of RY is independently 4-6 membered heteroaryl. In some embodiments, 1 of RY is 4-6 membered heteroaryl. In some embodiments, Y is substituted with 1 RY, and RY is 4-6 membered heteroaryl. In some embodiments, 1, 2, or 3 of RY is independently heteroaralkyl. In some embodiments, 1 of RY is independently heteroaralkyl. In some embodiments, 1, 2, or 3 of RY is independently 4-6 membered heterocyclyl optionally substituted with RY1. In some embodiments, 1 of RY is 4-6 membered heterocyclyl. In some embodiments, 1 of RY is 4-6 membered heterocyclyl substituted with RY1. In some embodiments, Y is substituted with 1 RY, and RY is 4-6 membered heterocyclyl substituted with RY1, where RY1 is hydroxyl. In some embodiments, RY is
Figure imgf000037_0003
In some embodiments, RY is
Figure imgf000037_0002
In some embodiments, Y is selected from the group consisting of:
Figure imgf000037_0001
,
Figure imgf000037_0004
In some embodiments, 1, 2, or 3 of RY is independently C1-C6 alkyl optionally substituted with –CO2RA or 4-6 membered heteroaryl optionally substituted with RY1. In some embodiments, 1, 2, or 3 of RY is independently C1-C6 alkyl substituted with –CO2RA or 4-6 membered heteroaryl optionally substituted with RY1. In some embodiments, 1, 2, or 3 of RY is independently C1-C6 alkyl substituted with –CO2RA or 4-6 membered heteroaryl substituted with RY1. In some embodiments, 1, 2, or 3 of RY is independently C1-C6 alkyl substituted with –CO2RA or 4-6 membered heteroaryl. In some embodiments, Y is substituted with 1 RY, and RY is C1-C6 alkyl substituted with –CO2RA. In some embodiments, Y is substituted with 1 RY, and RY is C1-C6 alkyl substituted with –CO2H. In some embodiments, 1 or 2 of RY is independently C1-C6 alkyl optionally substituted with –CO2RA or 4-6 membered heteroaryl optionally substituted with RY1. In some embodiments, 1 or 2 of RY is independently C1-C6 alkyl substituted with –CO2RA or 4-6 membered heteroaryl optionally substituted with RY1. In some embodiments, 1 or 2 of RY is independently C1-C6 alkyl substituted with –CO2RA or 4-6 membered heteroaryl substituted with RY1. In some embodiments, 1 or 2 of RY is independently C1-C6 alkyl substituted with – CO2RA or 4-6 membered heteroaryl. In some embodiments, 1 or 2 of RY is independently C1-C6 alkyl substituted with – CO2RA. In some embodiments, 1 or 2 of RY is independently C1-C6 alkyl substituted 4-6 membered heteroaryl optionally substituted with RY1. In some embodiments, 1 or 2 of RY is independently C1-C6 alkyl substituted with 4-6 membered heteroaryl substituted with RY1. In some embodiments, 1 or 2 of RY is independently C1-C6 alkyl substituted with 4-6 membered heteroaryl. In some embodiments, Y is substituted with 1 RY. In some embodiments, Y is substituted with 2 independently selected RY. In some embodiments, Y is substituted with 3 independently selected RY. In some embodiments, Y is substituted with 1 RY. In some embodiments, RY is halogen. In some embodiments, RY is chloro or fluoro. In some embodiments, RY is hydroxyl. In some embodiments, RY is is cyano. In some embodiments, RY is C1-C6 haloalkyl optionally substituted with hydroxyl. In some embodiments, RY is C1-C6 haloalkyl. In some embodiments, RY is C1-C6 alkoxy. In some embodiments, RY is C1-C6 haloalkoxy. In some embodiments, RY is C1-C6 hydroxyalkyl. In some embodiments, RY is -NHC(=O)RC. In some embodiments, RY is -C(=O)NHRY1. In some embodiments, RY is –CO2RA. In some embodiments, RY is -SO2NRFRG. In some embodiments, RY is -NHSO2RF. In some embodiments, RY is –S(=O)(=NRF)RG. In some embodiments, RY is –SO2(C1-C6 alkyl). In some embodiments, RY is -C(=O)NRARB. In some embodiments, RY is 4-6 membered heteroaryl. In some embodiments, RY is heteroaralkyl. In some embodiments, RY is 4-6 membered heterocyclyl optionally substituted with RY1. In some embodiments, RY is C1-C6 alkyl optionally substituted with –CO2RA or 4-6 membered heteroaryl optionally substituted with RY1. In some embodiments, 1, 2, or 3 of RY is independently C1-C6 alkyl. In some embodiments, 1 or 2 of RY is independently C1-C3 alkyl. In some embodiments, 1, 2, or 3 of RY is methyl. In some embodiments, RY1 is –SO2(C1-C6 alkyl). In some embodiments, RY1 is – SO2CH3. In some embodiments, RY1 is C1-C6 alkyl optionally substituted with oxo. In some embodiments, RY1 is C1-C6 alkyl substituted with oxo. In some embodiments, RY1 is acetyl, 1- oxoethyl, or 1-oxopropyl. In some embodiments, RY1 is C1-C6 alkyl. In some embodiments, RY1 is methyl. In some embodiments, RY1 is hydroxyl. In some embodiments, R4 is hydrogen. In some embodiments, R4 is C1-C6 alkyl. In some embodiments, R4 is methyl or ethyl. In some embodiments, R4 is methyl. In some embodiments, R4 is acrylamido. In some embodiments, R5 is hydrogen. In some embodiments, R5 is C1-C6 alkyl. In some embodiments, R5 is methyl or ethyl. In some embodiments, R5 is methyl. In some embodiments, R5 is cyano. In some embodiments, R5 is -NR5AR5B. In some embodiments, R5 is -NR5AC(=O)R5B. In some embodiments, R5 is -C(=O)NR5AR5B. In some embodiments, one of R5A and R5B is hydrogen and the other of R5A and R5B is C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 hydroxyalkyl. In some embodiments, one of R5A and R5B is C1-C6 alkyl and the other of R5A and R5B is C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 hydroxyalkyl. In some embodiments, each of R5A and R5B is hydrogen. In some embodiments, each of R5A and R5B is an independently selected C1-C6 alkyl. In some embodiments, each of R5A and R5B is methyl. In some embodiments, the C1-C6 hydroxyalkyl of R5A and R5B is hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, dihydroxypropyl or dihydroxybutyl. In some embodiments, R5 is acrylamido. In some embodiments, R6 is hydrogen. In some embodiments, R6 is halogen. In some embodiments, R6 is fluoro. In some embodiments, R6 is chloro. In some embodiments, R6 is C1-C6 alkyl. In some embodiments, R6 is methyl. In some embodiments, each of RA and RB are independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, or C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, or C1-C6 alkyl substituted with hydroxyl or C1-C6 alkoxy. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, or C1-C6 alkyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkoxy. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C3-C6 cycloalkyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C2-C6 alkenyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl substituted with hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl substituted with C1-C6 alkoxy. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1- C6 alkyl. In some embodiments, each of RA and RB are hydrogen. In some embodiments, each of RA and RB are an independently selected C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy. In some embodiments, each of RA and RB are an independently selected C1-C6 alkyl. In some embodiments, each of RA and RB are methyl. In some embodiments, RA and RB together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C1-C6 alkyl, and –C(=O)C1-C6 alkyl. In some embodiments, RA and RB together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl substituted with 1-2 substituents independently selected from halogen, C1-C6 alkyl, and –C(=O)C1-C6 alkyl. In some embodiments, RA and RB together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl substituted with halogen, C1-C6 alkyl, or – C(=O)C1-C6 alkyl. In some embodiments, RA and RB together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl substituted with 1-2 substitutents independently selected from fluoro, methyl, and acetyl. In some embodiments, RA and RB together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl. In some embodiments, RA and RB together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl. In some embodiments, each RC is independently C3-C6 cycloalkyl, -C(=O)NHRY1, or a C1-C6 alkyl substituted with -NRARB or with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl. In some embodiments, each RC is independently C3-C6 cycloalkyl, -C(=O)NHRY1, or a C1-C6 alkyl substituted with -NRARB or with 4-10 membered heterocyclyl substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl. In some embodiments, each RC is independently C3-C6 cycloalkyl, -C(=O)NHRY1, or a C1-C6 alkyl substituted with -NRARB or with 4-10 membered heterocyclyl. In some embodiments, each RC is independently C3-C6 cycloalkyl, -C(=O)NHRY1, or a C1-C6 alkyl. In some embodiments, each RC is independently C3-C6 cycloalkyl. In some embodiments, each RC is independently -C(=O)NHRY1. In some embodiments, each RC is independently C1-C6 alkyl optionally substituted with -NRARB or with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl. In some embodiments, each RC is independently C1-C6 alkyl substituted with -NRARB or with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl. In some embodiments, one of RD and RE is hydrogen and the other of RD and RE is hydroxyl, C1-C6 alkyl, or C1-C6 alkoxy. In some embodiments, one of RD and RE is hydrogen and the other of RD and RE is hydroxyl. In some embodiments, one of RD and RE is hydrogen and the other of RD and RE is C1-C6 alkyl. In some embodiments, one of RD and RE is hydrogen and the other of RD and RE is C1-C6 alkoxy. In some embodiments, one of RD and RE is hydrogen and the other of RD and RE is hydroxyl, methyl, or methoxy. In some embodiments, each of RD and RE is hydrogen. In some embodiments, each of RD and RE is an independently selected C1-C6 alkyl. In some embodiments, each of RD and RE is methyl. In some embodiments, one of RF and RG is hydrogen and the other of RF and RG is phenyl or C1-C6 alkyl optionally substituted with oxo or –NRARB. In some embodiments, one of RF and RG is hydrogen and the other of RF and RG is phenyl or C1-C6 alkyl substituted with oxo or –NRARB. In some embodiments, one of RF and RG is hydrogen and the other of RF and RG is phenyl or C1-C6 alkyl. In some embodiments, one of RF and RG is hydrogen and the other of RF and RG is phenyl. In some embodiments, one of RF and RG is hydrogen and the other of RF and RG is C1-C6 alkyl optionally substituted with oxo or –NRARB. In some embodiments, one of RF and RG is hydrogen and the other of RF and RG is C1-C6 alkyl substituted with oxo or –NRARB. In some embodiments, each of RF and RG is hydrogen. In some embodiments, each of RF and RG is an independently selected C1-C6 alkyl. In some embodiments, each of RF and RG is methyl. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A1):
Figure imgf000042_0001
or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-AA):
Figure imgf000043_0001
In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, is a compound of Formula (I-B):
Figure imgf000043_0002
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, is a compound of Formula (I-C):
Figure imgf000043_0003
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, is a compound of Formula (I-D):
Figure imgf000043_0004
or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, is a compound of Formula (I-E):
Figure imgf000044_0001
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-F):
Figure imgf000044_0002
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-FF):
Figure imgf000044_0003
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-G):
Figure imgf000045_0001
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-G1):
Figure imgf000045_0002
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-G2):
Figure imgf000045_0003
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-G3):
Figure imgf000046_0001
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, is a compound of Formula (I-G4):
Figure imgf000046_0002
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, is a compound of Formula (I-G5):
Figure imgf000046_0003
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, is a compound of Formula (I-G6):
Figure imgf000047_0001
or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-H):
Figure imgf000047_0002
or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 5-6 membered heterocyclyl or 5-6 membered heteroaryl; Q is N or CH; m is 0, 1, 2, or 3; n is 0, 1, or 2; and m+n is 0, 1, 2, or 3. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-HH):
Figure imgf000047_0003
or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 5-6 membered heterocyclyl or 5-6 membered heteroaryl; Q is N or CH; m is 0, 1, 2, or 3; n is 0, 1, or 2; and m+n is 0, 1, 2, or 3. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-I):
Figure imgf000048_0001
or a pharmaceutically acceptable salt thereof, wherein: Ring B is a 5-6 membered heterocyclyl, 6 membered heteroaryl, or phenyl; m is 0, 1, 2, or 3; n is 0, 1, or 2; and m+n is 0, 1, 2, or 3. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-II):
Figure imgf000048_0002
or a pharmaceutically acceptable salt thereof, wherein: Ring B is a 5-6 membered heterocyclyl, 6 membered heteroaryl, or phenyl; m is 0, 1, 2, or 3; n is 0, 1, or 2; and m+n is 0, 1, 2, or 3. Non-Limiting Exemplary Compounds In some embodiments, the compound is selected from the group consisting of the Compounds 1-1413, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is selected from the group consisting of the compounds delineated in Table A, or a pharmaceutically acceptable salt thereof.
Table A
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0001
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
Figure imgf000211_0001
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0001
Figure imgf000215_0001
Figure imgf000216_0001
Figure imgf000217_0001
Figure imgf000218_0001
Figure imgf000219_0001
Figure imgf000220_0001
Figure imgf000221_0001
Figure imgf000222_0001
Figure imgf000223_0001
Figure imgf000224_0001
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
Figure imgf000228_0001
Figure imgf000229_0001
Figure imgf000230_0001
Figure imgf000231_0001
Figure imgf000232_0001
Figure imgf000233_0001
Figure imgf000234_0001
Figure imgf000235_0001
Pharmaceutical Compositions Some embodiments provide a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. Methods of Treatment A “PI3Kα inhibitor” as used herein (e.g., compounds of Formula (I) and pharmaceutically acceptable salts thereof) includes any compound exhibiting PI3Kα inactivation activity (e.g., inhibiting or decreasing). In some embodiments, a PI3Kα inhibitor can be selective for a PI3Kα having one or more mutations. The ability of test compounds to act as inhibitors of PI3Kα may be demonstrated by assays known in the art. The activity of the compounds and compositions provided herein as PI3Kα inhibitors can be assayed in vitro, in vivo, or in a cell line. In vitro assays include assays that determine inhibition of the kinase. Alternate in vitro assays quantitate the ability of the inhibitor to bind to the protein kinase and can be measured either by radio labeling the compound prior to binding, isolating the compound/kinase complex and determining the amount of radio label bound, or by running a competition experiment where new compounds are incubated with the kinase bound to known radio ligands. Potency of a PI3Kα inhibitor as provided herein can be determined by EC50 value. A compound with a lower EC50 value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher EC50 value. Potency of a PI3Kα inhibitor as provided herein can also be determined by IC50 value. A compound with a lower IC50 value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher IC50 value. In some embodiments, the substantially similar conditions comprise determining a PI3Kα-dependent phosphorylation level, in vitro or in vivo. The selectivity between wild type PI3Kα and PI3Kα containing one or more mutations as described herein can also be measured using in vitro assays such as surface plasmon resonance and fluorence-based binding assays, and cellular assays such as the levels of pAKT, a biomarker of PI3Kα activity, and/or proliferation assays where cell proliferation is dependent on mutant PI3Kα kinase activity. In some embodiments, the compounds provided herein can exhibit potent and selective inhibition of PI3Kα. For example, the compounds provided herein can bind to the helical phosphatidylinositol kinase homology domain catalytic domain of PI3Kα. In some embodiments, the compounds provided herein can exhibit nanomolar potency against a PI3Kα kinase including one or more mutations, for example, the mutations in Table 1. In some embodiments, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, can selectively target PI3Kα. For example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can selectively target PI3Kα over another kinase or non-kinase target. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit greater inhibition of PI3Kα containing one or more mutations as described herein (e.g., one or more mutations as described in Table 1) relative to inhibition of wild type PI3Kα. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof can exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or 100-fold greater inhibition of PI3Kα containing one or more mutations as described herein relative to inhibition of wild type PI3Kα. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit up to 1,000-fold greater inhibition of PI3Kα containing one or more mutations as described herein relative to inhibition of wild type PI3Kα. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit up to 10,000-fold greater inhibition of PI3Kα having a combination of mutations described herein relative to inhibition of wild type PI3Kα. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit from about 2-fold to about 10-fold greater inhibition of PI3Kα containing one or more mutations as described herein relative to inhibition of wild type PI3Kα. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit from about 10-fold to about 100-fold greater inhibition of PI3Kα containing one or more mutations as described herein relative to inhibition of wild type PI3Kα. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit from about 100-fold to about 1,000-fold greater inhibition of PI3Kα containing one or more mutations as described herein relative to inhibition of wild type PI3Kα. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit from about 1000-fold to about 10,000-fold greater inhibition of PI3Kα containing one or more mutations as described herein relative to inhibition of wild type PI3Kα. Compounds of Formula (I), or pharmaceutically acceptable salts thereof, are useful for treating diseases which can be treated with a PI3Kα inhibitor, such as PI3Kα-associated diseases, e.g., proliferative disorders such as cancers, including hematological cancers and solid tumors (e.g., advanced or metastatic solid tumors). In some embodiments, the subject has been identified or diagnosed as having a cancer with a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity, or level of any of the same (a PI3Kα-associated cancer), for example, as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit. In some embodiments, the subject has a tumor that is positive for a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity, or level of any of the same (e.g., as determined using a regulatory agency-approved assay or kit). For example, the subject has a tumor that is positive for a mutation as described in Table 1. The subject can be a subject with a tumor(s) that is positive for a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity, or level of any of the same (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject can be a subject whose tumors have a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity, or a level of the same (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having a PI3Kα -associated cancer. In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity, or level of any of the same (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein). In certain embodiments, compounds of Formula (I), or pharmaceutically acceptable salts thereof, are useful for preventing diseases as defined herein such as cancer. The term “preventing” as used herein means to delay the onset, recurrence or spread, in whole or in part, of the disease as described herein, or a symptom thereof. The term “PI3Kα-associated disease” as used herein refers to diseases associated with or having a dysregulation of a PIK3CA gene, a PI3Kα protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a PIK3CA gene, or a PI3Kα protein, or the expression or activity or level of any of the same described herein). Non-limiting examples of a PI3Kα-associated disease include, for example, proliferative disorders such as cancer (e.g., PI3Kα-associated cancer). The term “PI3Kα-associated cancer” as used herein refers to cancers associated with or having a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity, or level of any of the same. Non-limiting examples of PI3Kα-associated cancer are described herein. The phrase “dysregulation of a PIK3CA gene, a PI3Kα protein, or the expression or activity or level of any of the same” refers to a genetic mutation (e.g., a mutation in a PIK3CA gene that results in the expression of a PI3Kα that includes a deletion of at least one amino acid as compared to a wild type PI3Kα, a mutation in a PIK3CA gene that results in the expression of PI3Kα with one or more point mutations as compared to a wild type PI3Kα, a mutation in a PIK3CA gene that results in the expression of PI3Kα with at least one inserted amino acid as compared to a wild type PI3Kα, a gene duplication that results in an increased level of PI3Kα in a cell, or a mutation in a regulatory sequence (e.g., a promoter and/or enhancer) that results in an increased level of PI3Kα in a cell), an alternative spliced version of PI3Kα mRNA that results in PI3Kα having a deletion of at least one amino acid in the PI3Kα as compared to the wild type PI3Kα), or increased expression (e.g., increased levels) of a wild type PI3Kα in a mammalian cell due to aberrant cell signaling and/or dysregulated autocrine/paracrine signaling (e.g., as compared to a control non-cancerous cell). As another example, a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity, or level of any of the same, can be a mutation in a PIK3CA gene that encodes a PI3Kα that is constitutively active or has increased activity as compared to a protein encoded by a PIK3CA gene that does not include the mutation. Non- limiting examples of PI3Kα point mutations/substitutions/insertions/deletions are described in Table 1. The term “wild type” describes a nucleic acid (e.g., a PIK3CA gene or a PI3Kα mRNA) or protein (e.g., a PI3Kα) sequence that is typically found in a subject that does not have a disease related to the reference nucleic acid or protein. The term “wild type PI3Kα” or “wild-type PI3Kα” describes a normal PI3Kα nucleic acid (e.g., a PIK3CA or PI3Kα mRNA) or protein that is found in a subject that does not have a PI3Kα-associated disease, e.g., a PI3Kα -associated cancer (and optionally also does not have an increased risk of developing a PI3Kα -associated disease and/or is not suspected of having a PI3Kα-associated disease), or is found in a cell or tissue from a subject that does not have a PI3Kα-associated disease, e.g., a PI3Kα -associated cancer (and optionally also does not have an increased risk of developing a PI3Kα -associated disease and/or is not suspected of having a PI3Kα-associated disease). Provided herein is a method of treating cancer (e.g., a PI3Kα-associated cancer) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. For example, provided herein are methods for treating PI3Kα-associated cancer in a subject in need thereof, comprising a) detecting a dysregulation of PIK3CA gene, a PI3Kα protein, or the expression or activity or level of any of the same in a sample from the subject; and b) administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation of a PIK3CA gene, a PI3Kα protein, or the expression or activity or level of any of the same includes one or more a PI3Kα protein substitutions/point mutations/insertions. Non- limiting examples of PI3Kα protein substitutions/insertions/deletions are described in Table 1. In some embodiments, the PI3Kα protein substitution/insertion/deletion is selected from the group consisting of E542A, E542G, E542K, E542Q, E542V, E545A, E545D, E545G, E545K, E545Q, M1043I, M1043L, M1043T, M1043V, H1047L, H1047Q, H1047R, H1047Y, G1049R, and combinations thereof. In some embodiments, the PI3Kα protein substitution / insertion / deletion is H1047X, where X is any amino acid other than H. In some embodiments, the PI3Kα protein substitution / insertion / deletion is E542X, where X is any amino acid other than E. In some embodiments, the PI3Kα protein substitution / insertion / deletion is E545X, where X is any amino acid other than E. In some embodiments, the dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same, includes a splice variation in a PI3Kα mRNA which results in an expressed protein that is an alternatively spliced variant of PI3Kα having at least one residue deleted (as compared to the wild type PI3Kα protein) resulting in a constitutive activity of a PI3Kα protein domain. In some embodiments, the dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same, includes at least one point mutation in a PIK3CA gene that results in the production of a PI3Kα protein that has one or more amino acid substitutions or insertions or deletions in a PIK3CA gene that results in the production of a PI3Kα protein that has one or more amino acids inserted or removed, as compared to the wild type PI3Kα protein. In some cases, the resulting mutant PI3Kα protein has increased activity, as compared to a wild type PI3Kα protein or a PI3Kα protein not including the same mutation. In some embodiments, the compounds described herein selectively inhibit the resulting mutant PI3Kα protein relative to a wild type PI3Kα protein or a PI3Kα protein not including the same mutation. In some embodiments of any of the methods or uses described herein, the cancer (e.g., PI3Kα-associated cancer) is selected from a hematological cancer and a solid tumor. In some embodiments of any of the methods or uses described herein, the cancer (e.g., PI3Kα-associated cancer) is selected from breast cancer (including both HER2+ and HER2- breast cancer, ER+ breast cancer, and triple negative breast cancer), uterine cancer (including endometrial cancer), lung cancer (including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLS, including adenocarcinoma lung cancer and squamous cell lung carcinoma)), esophageal squamous cell carcinoma, ovarian cancer, colorectal cancer, esophagastric adenocarcinoma, bladder cancer, head and neck cancer (including head and neck squamous cell cancers such as oropharyngeal squamous cell carcinoma), thyroid cancer, glioma, cervical cancer, lymphangioma, meningioma, melanoma (including uveal melanoma), kidney cancer, pancreatic neuroendocine neoplasms (pNETs), stomach cancer, esophageal cancer, acute myeloid leukemia, relapsed and refractory multiple myeloma, hepatocellular carcinoma, prostate cancer, Malignant Peripheral Nerve Sheath Tumor (MPNST), glioblastoma, cholangiocarcinoma, and pancreatic cancer. In some embodiments of any of the methods or uses described herein, the cancer (e.g., PI3Kα-associated cancer) is selected from breast cancer (including both HER2+ and HER2- breast cancer, ER+ breast cancer, and triple negative breast cancer), colon cancer, rectal cancer, colorectal cancer, ovarian cancer, lymphangioma, meningioma, head and neck squamous cell cancer (including oropharyngeal squamous cell carcinoma), melanoma (including uveal melanoma), kidney cancer, pancreatic neuroendocine neoplasms (pNETs), stomach cancer, esophageal cancer, acute myeloid leukemia, relapsed and refractory multiple myeloma, pancreatic cancer, lung cancer (including adenocarcinoma lung cancer and squamous cell lung carcinoma), and endometrial cancer. In some embodiments of any of the methods or uses described herein, the cancer (e.g., PI3Kα-associated cancer) is selected from breast cancer, SCLC, NSCLC, endometrial cancer, esophageal squamous cell carcinoma, ovarian cancer, colorectal cancer, esophagastric adenocarcinoma, bladder cancer, head and neck cancer, thyroid cancer, glioma, and cervical cancer.
In some embodiments of any of the methods or uses described herein, the PI3Kα- associated cancer is breast cancer. In some embodiments of any of the methods or uses described herein, the PI3Kα-associated cancer is colorectal cancer. In some embodiments of any of the methods or uses described herein, the PI3Kα-associated cancer is endometrial cancer. In some embodiments of any of the methods or uses described herein, the PI3Kα-associated cancer is lung cancer.
In some embodiments of any of the methods or uses described herein, the PI3Kα- associated cancer is selected from the cancers described in Table 1.
Table 1. PI3Kα Protein Amino Acid Substitutions/Insertions/DeletionsA
Figure imgf000242_0001
Figure imgf000243_0001
Figure imgf000244_0001
Exemplary Sequence of Human Phosphatidylinositol 4,5-bisphosphate 3-kinase isoform alpha (UniProtKB entry P42336) (SEQ ID NO: 1) MPPRPSSGEL WGIHLMPPRI LVECLLPNGM IVTLECLREA TLITIKHELF KEARKYPLHQ LLQDESSYIF VSVTQEAERE EFFDETRRLC DLRLFQPFLK VIEPVGNREE KILNREIGFA IGMPVCEFDM VKDPEVQDFR RNILNVCKEA VDLRDLNSPH SRAMYVYPPN VESSPELPKH IYNKLDKGQI IVVIWVIVSP NNDKQKYTLK INHDCVPEQV IAEAIRKKTR SMLLSSEQLK LCVLEYQGKY ILKVCGCDEY FLEKYPLSQY KYIRSCIMLG RMPNLMLMAK ESLYSQLPMD CFTMPSYSRR ISTATPYMNG ETSTKSLWVI NSALRIKILC ATYVNVNIRD IDKIYVRTGI YHGGEPLCDN VNTQRVPCSN PRWNEWLNYD IYIPDLPRAA RLCLSICSVK GRKGAKEEHC PLAWGNINLF DYTDTLVSGK MALNLWPVPH GLEDLLNPIG VTGSNPNKET PCLELEFDWF SSVVKFPDMS VIEEHANWSV SREAGFSYSH AGLSNRLARD NELRENDKEQ LKAISTRDPL SEITEQEKDF LWSHRHYCVT IPEILPKLLL SVKWNSRDEV AQMYCLVKDW PPIKPEQAME LLDCNYPDPM VRGFAVRCLE KYLTDDKLSQ YLIQLVQVLK YEQYLDNLLV RFLLKKALTN QRIGHFFFWH LKSEMHNKTV SQRFGLLLES YCRACGMYLK HLNRQVEAME KLINLTDILK QEKKDETQKV QMKFLVEQMR RPDFMDALQG FLSPLNPAHQ LGNLRLEECR IMSSAKRPLW LNWENPDIMS ELLFQNNEII FKNGDDLRQD MLTLQIIRIM ENIWQNQGLD LRMLPYGCLS IGDCVGLIEV VRNSHTIMQI QCKGGLKGAL QFNSHTLHQW LKDKNKGEIY DAAIDLFTRS CAGYCVATFI LGIGDRHNSN IMVKDDGQLF HIDFGHFLDH KKKKFGYKRE RVPFVLTQDF LIVISKGAQE CTKTREFERF QEMCYKAYLA IRQHANLFIN LFSMMLGSGM PELQSFDDIA YIRKTLALDK TEQEALEYFM KQMNDAHHGG WTTKMDWIFH TIKQHALN Also provided is a method for inhibiting PI3Kα activity in a cell, comprising contacting the cell with a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject having a cell having aberrant PI3Kα activity. In some embodiments, the cell is a cancer cell. In some embodiments, the cancer cell is any cancer as described herein. In some embodiments, the cancer cell is a PI3Kα-associated cancer cell. As used herein, the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" a PI3Kα protein with a compound provided herein includes the administration of a compound provided herein to an individual or subject, such as a human, having a PI3Kα protein, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the PI3Kα protein. Also provided herein is a method of inhibiting cell proliferation, in vitro or in vivo, comprising contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. Further provided herein is a method of increase cell death, in vitro or in vivo, comprising contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. Also provided herein is a method of increasing tumor cell death in a subject, comprising administering to the subject an effective compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount effective to increase tumor cell death. In some mebodiments, the PI3Kα is human PI3Kα. In some embodiments, the PI3Kα has one or more point mutations in the PIK3CA gene. In some embodiments, the point mtations include a substitution at amino acid position 1047 of a human PI3Kα protein. In some embodiments, the substitution is H1047R. When employed as pharmaceuticals, the compounds of Formula (I), including pharmaceutically acceptable salts thereof, can be administered in the form of pharmaceutical compositions as described herein. Embodiments 1. A compound of Formula (I):
Figure imgf000246_0001
or a pharmaceutically acceptable salt thereof, wherein: R1 is hydrogen, cyano, C3-C6 cycloalkyl, C1-C6 alkyl optionally substituted with phenyl optionally substituted with halogen, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 alkoxyalkyl; R2 is phenyl optionally substituted with 1-3 independently selected R2A, 5-10 membered heteroaryl optionally substituted with 1-3 independently selected R2A, 4-10 membered heterocyclyl optionally substituted with 1-3 independently selected R2A, 4-10 membered cycloalkyl optionally substituted with 1-3 independently selected R2A, C1-C6 alkoxyalkyl optionally substituted with –C(=O)NRARC, C1-C6 alkoxy optionally substituted with – C(=O)NRARC, or –O(R2B); each R2A is independently selected from: (i) halogen, (ii) cyano, (iii) hydroxyl, (iv) -NRARB, (v) -C(=O)NRARB, (vi)
Figure imgf000247_0001
(vii) -NHC(=O)RC, (viii) -C(=O)NRDRE, (ix) -C(=O)ORF, (x) -SO2RF, (xi) -NHSO2RF, (xii) -SO2NRFRG, (xiii) -NHC(=O)C1-C6 alkyl optionally substituted with NRARB, (xiv) C1-C6 haloalkyl, (xv) C1-C6 hydroxyalkyl, (xvi) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl and -NRARB, (xvii) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, -C(=O)NRARB, -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB, or C1- C6 alkyl optionally substituted with C1-C6 alkoxy or -NHC(=O)C1-C6 alkyl optionally substituted with C3-C16 cycloalkyl, (xviii) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C1-C6 alkoxy, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or – C(=O)C3-C6 cycloalkyl, (xix) C1-C6 alkoxy optionally substituted with -NRARB or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or –C(=O)C3-C6 cycloalkyl, and (xx) C3-C6 cycloalkyl optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl; R2B is phenyl optionally substituted with 1-4 independently selected R2A, 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R2A, 4-10 membered heterocyclyl optionally substituted with 1-4 independently selected R2A, 4-10 membered cycloalkyl optionally substituted with 1-4 independently selected R2A; each RA and RB is independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3- C6 cycloalkyl, C2-C6 alkenyl, –SO2(C1-C6 alkyl), and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy, or RA and RB together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C1-C6 alkyl, and –C(=O)C1-C6 alkyl; each RC is independently selected from C3-C6 cycloalkyl, -C(=O)NHRY1, or a C1-C6 alkyl optionally substituted with -NRARB or with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl; each RD and RE is independently selected from hydrogen, hydroxyl, C1-C6 alkyl, and C1- C6 alkoxy; each R3A and R3B is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl, or R3A and R3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group; R4 is hydrogen, C1-C6 alkyl, or acrylamido; R5 is hydrogen, C1-C6 alkyl, cyano, -NR5AR5B, -NR5AC(=O)R5B, or -C(=O)NR5AR5B; R5A and R5B are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 hydroxyalkyl; R6 is hydrogen, halogen, or C1-C6 alkyl; X is a bond, CH2, CH(CH3), C(CH3)2, or
Figure imgf000248_0001
Z is NR3B or O; Y is phenyl optionally substituted with 1-3 independently selected RY, naphthyl optionally substituted with 1-3 independently selected RY, or 5-10 membered heteroaryl optionally substituted with 1-3 independently selected RY; each RY is independently selected from: halogen, cyano, hydroxyl, C1-C6 haloalkyl optionally substituted with hydroxyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, - NHC(=O)RC, -C(=O)NHRY1, –CO2RA, -SO2NRFRG, -NHSO2RF, –S(=O)(=NRF)RG, –SO2(C1-C6 alkyl), -C(=O)NRARB, 4-6 membered heteroaryl, heteroaralkyl, 4-6 membered heterocyclyl optionally substituted with RY1, and C1-C6 alkyl optionally substituted with –CO2RA or 4-6 membered heteroaryl optionally substituted with RY1; RY1 is –SO2(C1-C6 alkyl), hydroxyl, or C1-C6 alkyl optionally substituted with oxo; and each RF and RG is independently selected from hydrogen, phenyl, and C1-C6 alkyl optionally substituted with oxo or –NRARB. 2. The compound of Embodiment 1, wherein R1 is hydrogen. 3. The compound of Embodiment 1, wherein R1 cyano. 4. The compound of Embodiment 1, wherein R1 is C3-C6 cycloalkyl. 5. The compound of Embodiment 1, wherein R1 is C1-C6 alkyl optionally substituted with phenyl optionally substituted with halogen. 6. The compound of Embodiment 1 or 5, wherein R1 is C1-C6 alkyl substituted with phenyl optionally substituted with halogen. 7. The compound of Embodiment 1 or 5-6, wherein R1 is C1-C6 alkyl substituted with phenyl substituted with halogen. 8. The compound of Embodiment 1 or 5-6, wherein R1 is C1-C6 alkyl substituted with phenyl. 9. The compound of Embodiment 1 or 5, wherein R1 is C1-C6 alkyl. 10. The compound of Embodiment 1, wherein R1 is C1-C6 thioalkyl. 11. The compound of Embodiment 1, wherein R1 is C1-C6 haloalkyl. 12. The compound of Embodiment 1, wherein R1 is C1-C6 alkoxy. 13. The compound of Embodiment 1, wherein R1 is C1-C6 alkoxyalkyl. 14. The compound of any one of Embodiments 1-13, wherein R2 is phenyl optionally substituted with 1-3 independently selected R2A. 15. The compound of any one of Embodiments 1-13, wherein R2 is 5-10 membered heteroaryl optionally substituted with 1-3 independently selected R2A. 16. The compound of any one of Embodiments 1-13, wherein R2 is 4-10 membered heterocyclyl optionally substituted with 1-3 independently selected R2A. 17. The compound of any one of Embodiments 1-13, wherein R2 is 4-10 membered cycloalkyl optionally substituted with 1-3 independently selected R2A or –O(R2B). 18. The compound of any one of Embodiments 1-17, wherein 1, 2, 3, or 4 of R2A are independently halogen. 19. The compound of any one of Embodiments 1-18, wherein 1, 2, 3, or 4 of R2A are independently cyano. 20. The compound of any one of Embodiments 1-19, wherein 1, 2, 3, or 4 of R2A are independently hydroxyl. 21. The compound of any one of Embodiments 1-20, wherein 1, 2, 3, or 4 of R2A are independently -NRARB. 22. The compound of any one of Embodiments 1-21, wherein 1, 2, 3, or 4 of R2A are independently -C(=O)NRARB. 23. The compound of any one of Embodiments 1-22, wherein 1, 2, 3, or 4 of R2A are independently
Figure imgf000250_0001
. 24. The compound of any one of Embodiments 1-23, wherein 1, 2, 3, or 4 of R2A are independently -NHC(=O)RC. 25. The compound of any one of Embodiments 1-24, wherein 1, 2, 3, or 4 of R2A are independently -C(=O)NRDRE. 26. The compound of any one of Embodiments 1-25, wherein 1, 2, 3, or 4 of R2A are independently -C(=O)ORF. 27. The compound of any one of Embodiments 1-26, wherein 1, 2, 3, or 4 of R2A are independently -SO2RF. 28. The compound of any one of Embodiments 1-27, wherein 1, 2, 3, or 4 of R2A are independently -NHSO2RF. 29. The compound of any one of Embodiments 1-28, wherein 1, 2, 3, or 4 of R2A are independently -SO2NRFRG. 30. The compound of any one of Embodiments 1-29, wherein 1, 2, 3, or 4 of R2A are independently -NHC(=O)C1-C6 alkyl optionally substituted with NRARB. 31. The compound of any one of Embodiments 1-30, wherein 1, 2, 3, or 4 of R2A are independently -NHC(=O)C1-C6 alkyl substituted with NRARB. 32. The compound of any one of Embodiments 1-31, wherein 1, 2, 3, or 4 of R2A are independently C1-C6 haloalkyl. 33. The compound of any one of Embodiments 1-32, wherein 1, 2, 3, or 4 of R2A are independently C1-C6 hydroxyalkyl. 34. The compound of any one of Embodiments 1-33, wherein 1, 2, 3, or 4 of R2A are independently 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl and -NRARB. 35. The compound of any one of Embodiments 1-34, wherein 1, 2, 3, or 4 of R2A are independently 5-10 membered heteroaryl substituted with 1-3 substituents independently selected from C1-C6 alkyl and -NRARB. 36. The compound of any one of Embodiments 1-35, wherein 1, 2, 3, or 4 of R2A are independently 5-10 membered heteroaryl. 37. The compound of any one of Embodiments 1-36, wherein 1, 2, 3, or 4 of R2A are independently 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, -C(=O)NRARB, or -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB. 38. The compound of any one of Embodiments 1-37, wherein 1, 2, 3, or 4 of R2A are independently 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, -C(=O)NRARB, or -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB. 39. The compound of any one of Embodiments 1-38, wherein 1, 2, 3, or 4 of R2A are independently 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, C1-C6 alkyl substituted with C1-C6 alkoxy, -C(=O)NRARB, or -NHC(=O)C1-C6 alkyl substituted with -NRARB. 40. The compound of any one of Embodiments 1-39, wherein 1, 2, 3, or 4 of R2A are independently 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, -C(=O)NRARB, -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB, or C1- C6 alkyl optionally substituted with C1-C6 alkoxy or -NHC(=O)C1-C6 alkyl optionally substituted with C3-C16 cycloalkyl. 41. The compound of any one of Embodiments 1-36, wherein 1, 2, 3, or 4 of R2A are independently 4-10 membered heterocyclyl. 42. The compound of any one of Embodiments 1-41, wherein 1, 2, 3, or 4 of R2A are independently C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or –C(=O)C3-C6 cycloalkyl. 43. The compound of any one of Embodiments 1-42, wherein 1, 2, 3, or 4 of R2A are independently C1-C6 alkyl substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or –C(=O)C3-C6 cycloalkyl. 44. The compound of any one of Embodiments 1-43, wherein 1, 2, 3, or 4 of R2A are independently C1-C6 alkyl substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C1-C6 alkoxy, and 4-10 membered heterocyclyl substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or –C(=O)C3-C6 cycloalkyl. 45. The compound of any one of Embodiments 1-43, wherein 1, 2, 3, or 4 of R2A are independently C1-C6 alkyl substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C1-C6 alkoxy, and 4-10 membered heterocyclyl. 46. The compound of any one of Embodiments 1-43, wherein 1, 2, 3, or 4 of R2A are independently C1-C6 alkyl. 47. The compound of any one of Embodiments 1-46, wherein 1, 2, 3, or 4 of R2A are independently C1-C6 alkoxy optionally substituted with -NRARB or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or –C(=O)C3-C6 cycloalkyl. 48. The compound of any one of Embodiments 1-47, wherein 1, 2, 3, or 4 of R2A are independently C1-C6 alkoxy substituted with -NRARB or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or –C(=O)C3-C6 cycloalkyl. 49. The compound of any one of Embodiments 1-48, wherein 1, 2, 3, or 4 of R2A are independently C1-C6 alkoxy substituted with -NRARB or 4-10 membered heterocyclyl substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or –C(=O)C3-C6 cycloalkyl. 50. The compound of any one of Embodiments 1-48, wherein 1, 2, 3, or 4 of R2A are independently C1-C6 alkoxy substituted with -NRARB or 4-10 membered heterocyclyl. 51. The compound of any one of Embodiments 1-47, wherein 1, 2, 3, or 4 of R2A are independently C1-C6 alkoxy. 52. The compound of any one of Embodiments 1-51, wherein 1, 2, 3, or 4 of R2A are independently C3-C6 cycloalkyl optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl. 53. The compound of any one of Embodiments 1-52, wherein 1, 2, 3, or 4 of R2A are independently C3-C6 cycloalkyl substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl. 54. The compound of any one of Embodiments 1-53, wherein 1, 2, 3, or 4 of R2A are independently C3-C6 cycloalkyl substituted with 4-10 membered heterocyclyl substituted with C1-C6 alkyl. 55. The compound of any one of Embodiments 1-53, wherein 1, 2, 3, or 4 of R2A are independently C3-C6 cycloalkyl substituted with 4-10 membered heterocyclyl. 56. The compound of any one of Embodiments 1-52, wherein 1, 2, 3, or 4 of R2A are independently C3-C6 cycloalkyl. 57. The compound of any one of Embodiments 1-13, wherein R2 is C1-C6 alkoxy optionally substituted with –C(=O)NRARC. 58. The compound of any one of Embodiments 1-13 or 57, wherein R2 is C1-C6 alkoxy substituted with –C(=O)NRARC. 59. The compound of any one of Embodiments 1-13 or 57, wherein R2 is C1-C6 alkoxy. 60. The compound of any one of Embodiments 1-13, R2 is C1-C6 alkoxyalkyl optionally substituted with –C(=O)NRARC. 61. The compound of any one of Embodiments 1-13, R2 is C1-C6 alkoxyalkyl. 62. The compound of any one of Embodiments 1-61, wherein X is a bond. 63. The compound of any one of Embodiments 1-61, wherein X is CH2. 64. The compound of any one of Embodiments 1-61, wherein X is CH(CH3). 65. The compound of any one of Embodiments 1-61, wherein X is C(CH3)2. 66. The compound of any one of Embodiments 1-61, wherein X is
Figure imgf000254_0001
. 67. The compound of any one of Embodiments 1-66, wherein Z is O. 68. The compound of any one of Embodiments 1-66, wherein R3A is hydrogen. 69. The compound of any one of Embodiments 1-66, wherein R3A is C1-C6 alkyl. 70. The compound of any one of Embodiments 1-67, wherein R3A is methyl. 71. The compound of any one of Embodiments 1-66, wherein R3A is C1-C6 alkoxy. 72. The compound of any one of Embodiments 1-66, R3A is C1-C6 haloalkyl. 73. The compound of any one of Embodiments 1-66, wherein Z is NR3B. 74. The compound of Embodiment 73, wherein one of R3A and R3B is hydrogen and the other of R3A and R3B is C1-C6 alkyl. 75. The compound of Embodiment 73-74, wherein one of R3A and R3B is hydrogen and the other of R3A and R3B is methyl. 76. The compound of Embodiment 73, wherein each of R3A and R3B is hydrogen. 77. The compound of Embodiment 73, wherein each of R3A and R3B is an independently selected C1-C6 alkyl. 78. The compound of Embodiment 73 or 77, wherein each of R3A and R3B is methyl. 79. The compound of Embodiment 73, wherein one of R3A and R3B is hydrogen and the other of R3A and R3B is C1-C6 alkoxy. 80. The compound of Embodiment 73, wherein one of R3A and R3B is C1-C6 alkyl and the other of R3A and R3B is C1-C6 alkoxy. 81. The compound of Embodiment 73, wherein each of R3A and R3B is C1-C6 alkoxy. 82. The compound of Embodiment 73, wherein one of R3A and R3B is hydrogen and the other of R3A and R3B is C1-C6 haloalkyl. 83. The compound of Embodiment 73, wherein one of R3A and R3B is C1-C6 alkyl and the other of R3A and R3B is C1-C6 haloalkyl. 84. The compound of Embodiment 73, wherein each of R3A and R3B is C1-C6 haloalkyl. 85. The compound of Embodiment 73, wherein R3A and R3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group. 86. The compound of any one of Embodiments 1-85, wherein Y is phenyl optionally substituted with 1-3 independently selected RY. 87. The compound of any one of Embodiments 1-85, wherein Y is naphthyl optionally substituted with 1-3 independently selected RY. 88. The compound of any one of Embodiments 1-85, wherein Y is 5-10 membered heteroaryl optionally substituted with 1-3 independently selected RY. 89. The compound of any one of Embodiments 1-88, wherein 1, 2, or 3 of RY is independently halogen. 90. The compound of any one of Embodiments 1-89, wherein 1, 2, or 3 of RY is hydroxyl. 91. The compound of any one of Embodiments 1-90, wherein 1, 2, or 3 of RY is cyano. 92. The compound of any one of Embodiments 1-91, wherein 1, 2, or 3 of RY is independently C1-C6 haloalkyl. 93. The compound of any one of Embodiments 1-92, wherein 1, 2, or 3 of RY is independently C1-C6 alkoxy. 94. The compound of any one of Embodiments 1-93, wherein 1, 2, or 3 of RY is independently C1-C6 haloalkoxy. 95. The compound of any one of Embodiments 1-94, wherein 1, 2, or 3 of RY is independently C1-C6 hydroxyalkyl. 96. The compound of any one of Embodiments 1-95, wherein 1, 2, or 3 of RY is independently -NHC(=O)RC. 97. The compound of any one of Embodiments 1-96, wherein 1, 2, or 3 of RY is independently -C(=O)NHRY1. 98. The compound of any one of Embodiments 1-97, wherein 1, 2, or 3 of RY is independently –CO2RA. 99. The compound of any one of Embodiments 1-98, wherein 1, 2, or 3 of RY is independently -SO2NRFRG. 100. The compound of any one of Embodiments 1-99, wherein 1, 2, or 3 of RY is independently -NHSO2RF. 101. The compound of any one of Embodiments 1-100, wherein 1, 2, or 3 of RY is independently –S(=O)(=NRF)RG. 102. The compound of any one of Embodiments 1-101, wherein 1, 2, or 3 of RY is independently –SO2(C1-C6 alkyl). 103. The compound of any one of Embodiments 1-102, wherein 1, 2, or 3 of RY is independently -C(=O)NRARB. 104. The compound of any one of Embodiments 1-103, wherein 1, 2, or 3 of RY is independently 4-6 membered heteroaryl. 105. The compound of any one of Embodiments 1-104, wherein 1, 2, or 3 of RY is independently heteroaralkyl. 106. The compound of any one of Embodiments 1-105, wherein 1, 2, or 3 of RY is independently 4-6 membered heterocyclyl. 107. The compound of any one of Embodiments 1-106, wherein 1, 2, or 3 of RY is independently C1-C6 alkyl optionally substituted with –CO2RA or 5-6 membered heteroaryl optionally substituted with RY1. 108. The compound of any one of Embodiments 1-107, wherein 1, 2, or 3 of RY is independently C1-C6 alkyl substituted with –CO2RA or 5-6 membered heteroaryl optionally substituted with RY1. 109. The compound of any one of Embodiments 1-108, wherein 1, 2, or 3 of RY is independently C1-C6 alkyl substituted with –CO2RA or 5-6 membered heteroaryl substituted with RY1. 110. The compound of any one of Embodiments 1-107, wherein 1, 2, or 3 of RY is independently C1-C6 alkyl substituted with –CO2RA or 5-6 membered heteroaryl. 111. The compound of any one of Embodiments 1-107, wherein 1, 2, or 3 of RY is independently C1-C6 alkyl. 112. The compound of any one of Embodiments 1-88 or 107-109, wherein RY1 is – SO2(C1-C6 alkyl). 113. The compound of any one of Embodiments 1-88 or 107-109, wherein RY1 is C1- C6 alkyl optionally substituted with oxo. 114. The compound of any one of Embodiments 1-107, wherein 1, 2, or 3 of RY1 is hydroxyl. 115. The compound of any one of Embodiments 1-10114, wherein R4 is hydrogen. 116. The compound of any one of Embodiments 1-114, wherein R4 is C1-C6 alkyl. 117. The compound of any one of Embodiments 1-114, wherein R4 is acrylamido. 118. The compound of any one of Embodiments 1-117, wherein R5 is hydrogen. 119. The compound of any one of Embodiments 1-117, wherein R5 is C1-C6 alkyl. 120. The compound of any one of Embodiments 1-117, wherein R5 is cyano. 121. The compound of any one of Embodiments 1-117, wherein R5 is -NR5AR5B. 122. The compound of any one of Embodiments 1-117, wherein R5 is -C(=O)NR5AR5B. 123. The compound of any one of Embodiments 1-117, wherein R5 is -NR5AC(=O)R5B. 124. The compound of any one of Embodiments 1-117 or 121-123, wherein one of R5A and R5B is hydrogen and the other of R5A and R5B is C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 hydroxyalkyl. 125. The compound of any one of Embodiments 1-117 or 121-123, wherein one of R5A and R5B is C1-C6 alkyl and the other of R5A and R5B is C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 hydroxyalkyl. 126. The compound of any one of Embodiments 1-103 or 121-123, wherein each of R5A and R5B is hydrogen. 127. The compound of any one of Embodiments 1-117 or 121-123, wherein each of R5A and R5B is an independently selected C1-C6 alkyl. 128. The compound of any one of Embodiments 1-127, wherein R6 is hydrogen. 129. The compound of any one of Embodiments 1-127, wherein R6 is halogen. 130. The compound of any one of Embodiments 1-127, wherein R6 is C1-C6 alkyl. 131. The compound of any one of Embodiments 1-130, wherein each of RA and RB are independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy. 132. The compound of any one of Embodiments 1-131, wherein one of RA and RB is hydrogen and the other of RA and RB is hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, or C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy. 133. The compound of any one of Embodiments 1-132, wherein one of RA and RB is hydrogen and the other of RA and RB is hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, or C1-C6 alkyl substituted with hydroxyl or C1-C6 alkoxy. 134. The compound of any one of Embodiments 1-132, wherein one of RA and RB is hydrogen and the other of RA and RB is hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, or C1-C6 alkyl. 135. The compound of any one of Embodiments 1-130, wherein RA and RB together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C1-C6 alkyl, and –C(=O)C1-C6 alkyl. 136. The compound of any one of Embodiments 1-130 or 135, wherein RA and RB together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl substituted with 1-2 substituents independently selected from halogen, C1-C6 alkyl, and – C(=O)C1-C6 alkyl. 137. The compound of any one of Embodiments 1-130 or 135, wherein RA and RB together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl. 138. The compound of any one of Embodiments 1-125, wherein each RC is independently C3-C6 cycloalkyl, -C(=O)NHRY1, or a C1-C6 alkyl substituted with -NRARB or with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl. 139. The compound of any one of Embodiments 1-138, wherein each RC is independently C3-C6 cycloalkyl, -C(=O)NHRY1, or a C1-C6 alkyl substituted with -NRARB or with 4-10 membered heterocyclyl substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl. 140. The compound of any one of Embodiments 1-139, wherein each RC is independently C3-C6 cycloalkyl, -C(=O)NHRY1, or a C1-C6 alkyl substituted with -NRARB or with 4-10 membered heterocyclyl. 141. The compound of any one of Embodiments 1-138, wherein each RC is independently C3-C6 cycloalkyl, -C(=O)NHRY1, or a C1-C6 alkyl. 142. The compound of any one of Embodiments 1-141, wherein one of RD and RE is hydrogen and the other of RD and RE is hydroxyl, C1-C6 alkyl, or C1-C6 alkoxy. 143. The compound of any one of Embodiments 1-141, wherein each of RD and RE is hydrogen. 144. The compound of any one of Embodiments 1-141, wherein each of RD and RE is an independently selected C1-C6 alkyl. 145. The compound of any one of Embodiments 1-144, wherein one of RF and RG is hydrogen and the other of RF and RG is phenyl or C1-C6 alkyl optionally substituted with oxo or –NRARB. 146. The compound of any one of Embodiments 1-144, wherein one of RF and RG is hydrogen and the other of RF and RG is phenyl or C1-C6 alkyl substituted with oxo or –NRARB. 147. The compound of any one of Embodiments 1-144, wherein one of RF and RG is hydrogen and the other of RF and RG is phenyl or C1-C6 alkyl. 148. The compound of any one of Embodiments 1-144, wherein each of RF and RG is hydrogen. 149. The compound of any one of Embodiments 1-144, wherein each of RF and RG is an independently selected C1-C6 alkyl. 150. A compound selected from the group consisting of the compounds in Table A, or a pharmaceutically acceptable salt thereof. 151. A pharmaceutical composition comprising a compound of any one of Embodiments 1-150, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. 152. A method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1-150, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 151. 153. A method for treating cancer in a subject in need thereof, the method comprising (a) determining that the cancer is associated with a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same; and (b) administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1-150, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 151. 154. A method of treating a PI3Kα-associated cancer in a subject, comprising administering to a subject identified or diagnosed as having a PI3Kα-associated cancer a therapeutically effective amount of a compound of any one of Embodiments 1-150 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 151. 155. A method for inhibiting mutant PI3Kα activity in a mammalian cell, the method comprising contacting the mammalian cell with an effective amount of a compound of any one of Embodiments 1-150, or a pharmaceutically acceptable salt thereof. EXAMPLES Compound Preparation The general methods for the preparation of the compounds of Formula (I) have been described in an illustrative manner and is intended to be description, rather than of limitation. Thus, it will be appreciated that conditions such as choice of solvent, temperature of reaction, volumes, reaction time may vary while still producing the desired compounds. In addition, it will be appreciated that many of the reagents provided in the following examples may be substituted with other suitable reagents. See, e.g., Smith & March, Advanced Organic Chemistry, 7th Ed. (2013). Such changes and modifications, including without limitation, those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and / or methods of use provided herein, may be made without departing from the spirit and scope thereof. The starting materials used for the syntheses are either synthesized or obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, Fluka, Acros Organics, Alfa Aesar, Enamine, Strem, VWR Scientific, and the like. Nuclear Magnetic Resonance (NMR) analysis was conducted using a Bruker AVANCE III HD (300 or 400) MHz spectrometer or Bruker AVANCE NEO 400 MHz spectrometer with an appropriate deuterated solvent. LCMS spectra were obtained on a Shimadzu LCMS-2020 with electrospray ionization in positive ion detection mode with 20ADXR pump, SIL-20ACXR autosampler, CTO-20AC column oven, M20A PDA Detector and LCMS 2020 MS detector. Example 1: Preparation of rel-(R)-2-((1-(7-methyl-4-oxo-2-(pyridin-4-yl)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 268) and rel-(R)-2-((1- (7-methyl-4-oxo-2-(pyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 269)
Figure imgf000261_0001
Step 1: Preparation of rel-(R)-2-((1-(7-methyl-4-oxo-2-(pyridin-4-yl)-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 268) and rel-(R)-2-((1-(7-methyl-4-oxo- 2-(pyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 269) 2-((1-(7-methyl-4-oxo-2-(pyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (70 mg) was isolated by Prep-chiral-HPLC with the following conditions : Column: Chiral ART Cellulose-SA, 2*25 cm, 5 μm; Mobile Phase A: Hex (0.1% FA)--HPLC, Mobile Phase B: EtOH--HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B (isocratic) in 12 min; Wave Length: 205/254 nm; RT1(min): 5.37; RT2(min): 8.8; Sample Solvent: MeOH: DCM=1: 1--HPLC; Injection Volume: 0.8 mL; Number Of Runs: 5. The 1st eluting fraction was concentrated and lyophilized to afford rel-(R)-2-((1-(7-methyl-4-oxo-2- (pyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 268; 21.9 mg, 31.28%, ee=99.86%) as a white solid, and the 2nd eluting fraction was concentrated and lyophilized to afford rel-(R)-2-((1-(7-methyl-4-oxo-2-(pyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin- 9-yl)ethyl)amino)benzoic acid (Compound 269; 19.8 mg, 28.28%, ee=99.71%) as a white solid. Compound 268: 1H NMR (300 MHz, DMSO-d6) δ 8.86 – 8.67 (m, 3H), 8.57 (s, 1H), 8.28 – 8.16 (m, 2H), 7.88 – 7.77 (m, 2H), 7.28 – 7.11 (m, 2H), 6.61 – 6.49 (m, 1H), 6.44 (d, J = 8.5 Hz, 1H), 5.57 (d, J = 7.0 Hz, 1H), 2.37 (s, 3H), 1.69 (d, J = 6.6 Hz, 3H). LC-MS: (ES+H, m/z): [M+H]+ = 401.1 Compound 269: 1H NMR (300 MHz, DMSO-d6) δ 8.89 – 8.71 (m, 3H), 8.53 (d, J = 6.4 Hz, 1H), 8.26 – 8.14 (m, 2H), 7.90 – 7.76 (m, 2H), 7.27 – 7.10 (m, 2H), 6.55 (t, J = 7.6 Hz, 1H), 6.44 (d, J = 8.5 Hz, 1H), 5.64 – 5.47 (m, 1H), 2.37 (s, 3H), 1.70 (d, J = 6.6 Hz, 3H). LC-MS: (ES+H, m/z): [M+H]+ = 401.1 Example 2: Preparation of rel-2-{[(1R)-1-(2-{4-[(4-cyclopropanecarbonylpiperazin- 1-yl)methyl]-3-fluorophenyl}-7-methyl-4-oxopyrido[1,2-a]pyrimidin-9- yl)ethyl]amino}benzoic acid (Compound 420) and rel-2-{[(1R)-1-(2-{4-[(4- cyclopropanecarbonylpiperazin-1-yl)methyl]-3-fluorophenyl}-7-methyl-4-oxopyrido[1,2- a]pyrimidin-9-yl)ethyl]amino}benzoic acid (Compound 421)
Figure imgf000262_0001
2-{[1-(2-{4-[(4-cyclopropanecarbonylpiperazin-1-yl)methyl]-3-fluorophenyl}-7-methyl- 4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino}benzoic acid (140 mg, 0.240 mmol, 1 equiv) was isolated by prep-chiral-HPLC with the following conditions: Column: CHIRAL ART Cellulose- SB, 3*25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: IPA(0.1% 2M NH3-MEOH); Flow rate: 100 mL/min; Gradient: isocratic 50% B; Column Temperature (℃): 35; Back Pressure (bar): 100; Wave Length: 220/278 nm; RT1(min): 4.85; RT2(min): 6, 2(min): ; Sample Solvent: IPA; Injection Volume: 2 mL; Number Of Runs: 8. The 1st eluting fraction was concentrated and lyophilized to afford (isomer 1) rel-2-{[(1R)-1-(2-{4-[(4-cyclopropanecarbonylpiperazin-1- yl)methyl]-3-fluorophenyl}-7-methyl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino}benzoic acid (Compound 420; 40.8 mg, 29.08%, ee=100%). The 2nd eluting fraction was concentrated and lyophilized to afford (isomer 2) rel-2-{[(1R)-1-(2-{4-[(4-cyclopropanecarbonylpiperazin-1- yl)methyl]-3-fluorophenyl}-7-methyl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino}benzoic acid (Compound 421; 35.1 mg, 24.87%, ee=97.2%) Compound 420: 1H NMR (300 MHz, DMSO-d6) δ 8.75 (s, 2H), 8.17 – 8.02 (m, 2H), 7.90 – 7.81 (m, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.13 (d, J = 14.0 Hz, 2H), 6.54 (t, J = 7.5 Hz, 1H), 6.38 (d, J = 8.4 Hz, 1H), 5.56 (q, J = 7.5 Hz, 1H), 3.65 (d, J = 12.1 Hz, 4H), 3.47 (s, 2H), 2.49 – 2.26 (m, 7H), 2.02-1.88 (m, 1H), 1.66 (d, J = 6.5 Hz, 3H), 0.87-0.59 (m, 4H). LC-MS: (ES+H, m/z): [M+H]+ = 584.2 Compound 421: 1H NMR (300 MHz, DMSO-d6) δ 8.74 (s, 2H), 8.19 – 7.99 (m, 2H), 7.96-7.87 (m, 1H), 7.77 (d, J = 2.0 Hz, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.09 (s, 2H), 6.52 (t, J = 7.5 Hz, 1H), 6.32 (d, J = 8.4 Hz, 1H), 5.54 (q, J = 6.4 Hz, 1H), 3.64 (d, J = 13.0 Hz, 4H), 3.47 (s, 2H), 2.48 – 2.22 (m, 7H), 2.00-1.84 (m, 1H), 1.64 (d, J = 6.5 Hz, 3H), 0.79-0.61 (m, 4H). LC- MS: (ES+H, m/z): [M+H]+ = 584.2 Example 3: Preparation of (R)-2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-7-methyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 739) and (S)-2- ((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (Compound 740)
Figure imgf000263_0001
Step 1: Synthesis of 9-bromo-2-hydroxy-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one A solution of 3-bromo-5-methylpyridin-2-amine (20 g, 108 mmol) in acetone (200 mL) was added bis(2,4,6-trichlorophenyl) malonate (55 g, 119 mmol). The reaction mixture was heated to 60 °C for 2 h under N2 atmosphere. After cooling to room temperature, the reaction was filtered to give the title compound (19.5 g, 72%) as a yellow solid that required no further purification.1H NMR (400 MHz, DMSO-d6): δ 11.74 (s, 1H), 8.74 (d, J = 2.0 Hz, 1H), 8.33 (d, J = 2.0 Hz, 1H), 5.50 (s, 1H), 2.34 (s, 3H). MS: m/z 254.8 (M+H+). Step 2: Synthesis of 2-(benzyloxy)-9-bromo-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one A solution of 9-bromo-2-hydroxy-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (12.5 g, 49 mmol), K2CO3 (13.5 g, 98 mmol) and TBAI (1.8 mg, 4.9 mmol) in DMF (120 mL) was added BnBr (6.71 g, 39.2 mmol). The reaction was heated to 65 ºC for 2 h under N2 atmosphere. After cooling to room temperature, the reaction was added water (200 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 20% EtOAc in petroleum ether) to give the title compound (4 g, 23%) as a white solid.1H NMR (400 MHz, CDCl3): δ 8.86 (s, 1H), 7.98 (s, 1H), 7.57 - 7.49 (m, 2H), 7.40 - 7.30 (m, 3H), 5.85 (s, 1H), 5.52 (s, 2H), 2.40 (s, 3H) MS: m/z 345.0 (M+H+). Step 3: Synthesis of 9-acetyl-2-(benzyloxy)-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one A mixture of 2-(benzyloxy)-9-bromo-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (3 g, 8.7 mmol), tributyl(1-ethoxyvinyl)stannane (7.85 g, 21.7 mmol) and Pd(dppf)Cl2 (509 mg, 0.7 mmol) in dioxane (30 mL) was degassed and purged with N2 for 3 times. The reaction mixture was stirred at 90 °C for 16 h under N2 atmosphere. After cooling to room temperature, HCl (3 mL, 1 M) was added. The mixture was stirred at room temperature for 0.5 h. The reaction mixture was added 50 mL 10% KF aqueous solution, stirred at room temperature for 2 h. The mixture was extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give the title compound (1.39 g, 51%) as a white solid.1H NMR (400 MHz, DMSO-d6): δ 8.94 (s, 1H), 8.07 (s, 1H), 7.47 - 7.42 (m, 2H), 7.42 - 7.30 (m, 3H), 5.77 (s, 1H), 5.41 (s, 2H), 2.70 (s, 3H), 2.41 (s, 3H). MS: m/z 309.2 (M+H+). Step 4: Synthesis of 9-(1-aminoethyl)-2-(benzyloxy)-7-methyl-4H-pyrido[1,2- a]pyrimidin-4-one To a solution of 9-acetyl-2-(benzyloxy)-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (1 g, 3.2 mmol), NH4OAc (3.75 g, 48.6 mmol) in MeOH (10 mL), NaBH3CN (610 mg, 9.7 mmol) was added. The reaction was heated to 40 ºC for 16 h under N2 atmosphere. After cooling to room temperature, the reaction was diluted with water (200 mL), extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 10% MeOH in DCM) to give the title compound (510 mg, 50%) as a white solid.1H NMR (400 MHz, DMSO-d6): δ 8.79 (s, 1H), 8.02 (s, 1H), 7.54 - 7.26 (m, 5H), 6.42 - 6.09 (m, 2H), 5.77 (s, 1H), 5.54 - 5.38 (m, 2H), 4.99 - 4.75 (m, 1H), 2.41 (s, 3H), 1.45 (d, J = 6.8 Hz, 3H). MS: m/z 310.2 (M+H+). Step 5: Synthesis of tert-butyl 2-((1-(2-(benzyloxy)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate A mixture of 9-(1-aminoethyl)-2-(benzyloxy)-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (500 mg, 1.6 mmol), tert-butyl 2-bromobenzoate (540 mg, 2.1 mmol), Cs2CO3 (1.05 g, 3.2 mmol) , Pd2(dba)3 (148 mg, 0.16 mmol) and Xantphos (140 mg, 0.24 mmol) in dioxane (8 mL), the reaction mixture was stirred at 100 °C for 16 h under N2 atmosphere. After cooling to room temperature, the reaction was filtered and the filtrate was concentrated. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 20% EtOAc in petroleum ether) to give the title compound (250 mg, 31%) as a white solid.1H NMR (400MHz, DMSO-d6): δ 8.73 (s, 1H), 8.30 - 8.15 (m, 1H), 7.80 (d, J = 2.0 Hz, 1H), 7.79 - 7.74 (m, 1H), 7.50 - 7.42 (m, 2H), 7.41 - 7.34 (m, 2H), 7.34 - 7.28 (m, 1H), 7.21 - 7.13 (m, 1H), 6.61 - 6.51 (m, 1H), 6.31 (d, J = 8.8 Hz, 1H), 5.77 (s, 1H), 5.58 - 5.45 (m, 2H), 5.33 - 5.24 (m, 1H), 2.32 (s, 3H), 1.56 (s, 9H), 1.53 (d, J = 6.8 Hz, 3H). MS: m/z 486.3 (M+H+). Step 6: Synthesis of tert-butyl 2-((1-(2-hydroxy-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate To a solution of tert-butyl 2-((1-(2-(benzyloxy)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (2.7 g, 5.6 mmol) in MeOH (30 mL) was added wet Pd/C (3 g, 10% Pd, 50% wet with water). The reaction was stirred at room temperature for 0.5 h under H2 atmosphere (15 psi). The reaction was filtered through diatomaceous earth and the filtrate was concentrated to afford the title compound (1.7 g, 77%) as yellow oil that required no further purification.1H NMR (400 MHz, DMSO-d6): δ 8.74 - 8.59 (m, 1H), 8.17 (d, J = 6.0 Hz, 1H), 7.80 - 7.74 (m, 1H), 7.71 - 7.65 (m, 1H), 7.26 - 7.14 (m, 1H), 6.59 - 6.50 (m, 1H), 6.27 (d, J = 8.4 Hz, 1H), 5.53 (s, 1H), 5.35 - 5.24 (m, 1H), 2.27 (s, 3H), 1.61 - 1.49 (m, 12H). MS: m/z 396.2 (M+H+). Step 7: Synthesis of tert-butyl 2-((1-(7-methyl-4-oxo-2-(((trifluoromethyl)sulfonyl)oxy)- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate To a solution of tert-butyl 2-((1-(2-hydroxy-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin- 9-yl)ethyl)amino)benzoate (500 mg, 1.3 mmol) in DCM (10 mL) was added pyridine (300 mg, 3.8 mmol) and Tf2O (535 mg, 1.9 mmol).The mixture was stirred at 0 °C for 2 h. After the reaction was completed, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 10% EtOAc in petroleum ether) to give the title compound (510 mg, 50%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.85 - 8.22 (m, 1H), 8.21 (d, J = 6.6 Hz, 1H), 8.01 - 7.96 (m, 1H), 7.79 - 7.78 (m, 1H), 7.19 - 7.15 (m, 1H), 6.59 - 6.56 (m, 1H), 6.52 (s, 1H), 6.29 (d, J = 8.8 Hz, 1H), 5.23 - 5.17 (m, 1H), 2.40 (s, 3H), 1.59 - 1.57 (m, 12H). MS: m/z 528.1 (M+H+). Step 8: Synthesis of tert-butyl 2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-7-methyl-4-oxo- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate To a mixture of tert-butyl 2-((1-(7-methyl-4-oxo-2-(((trifluoromethyl)sulfonyl)oxy)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (300 mg, 569 umol), K2CO3 (236 mg, 1.7 mmol) and 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (217 mg, 796 umol) (prepared according to the procedure in WO201755305) in dioxane (5 mL) and water (0.5 mL), Pd(PPh3)4 (66 mg, 57 umol) was added. The reaction mixture was heated to 100 °C and stirred for 2 h under N2 atmosphere. The reaction was diluted with water (20 mL) and ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel eluting with (3% MeOH in DCM) to afford the title compound (290 mg, 97%) as a yellow solid.1H NMR (400 MHz, DMSO-d6): δ 8.76 (s, 1H), 8.70 (s, 1H), 8.27 - 8.38 (m, 2H), 7.85 - 7.79 (m, 1H), 7.75 - 7.66 (m, 1H) , 7.23 - 7.19 (m, 1H), 7.16 (s, 1H), 6.58 - 6.53 (m, 1H), 6.52 - 6.48 (m, 1H), 5.60 - 5.55 (m, 1H), 4.00 (s, 3H), 2.56 (s, 3H), 2.35 (s, 3H), 1.74 (d, J = 6.4 Hz, 3H), 1.53 (s, 9H). MS: m/z 524.2 (M+H+). Step 9: Synthesis of 2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid To a mixture of tert-butyl 2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (50 mg, 95 umol) in DCM (3 mL) was added TFA (0.5 mL, 6.9 mmol). The reaction mixture was stirred at room temperature for 16 h. The mixture was concentrated and the residue was purified by reverse phase chromatography (acetonitrile 51% - 81% / 0.225% formic acid in water) to give the title compound (5 mg, 11%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.70 ( s, 1H), 8.76 (s, 1H), 8.69 (s, 1H), 8.56 - 8.48 (m, 1H), 8.40 - 8.32 (m, 1H), 7.86 - 7.82 (m, 1H), 7.79 - 7.76 (m, 1H), 7.69 - 7.65 (m, 1H), 7.24 – 7.20 (m, 1H), 7.15 (s, 1H), 6.57 - 6.54 (m, 1H), 6.50 - 6.47 (m, 1H), 5.63 - 5.58 (m, 1H), 4.00 (s, 3H), 2.56 (s, 3H), 2.35 (s, 3H), 1.72 (d, J = 6.8 Hz, 3H). MS: m/z 468.1 (M+H+). Step 10: Synthesis of (R)-2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 739) and (S)-2-((1-(2-(1,3- dimethyl-1H-indazol-5-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (Compound 740) 2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (200 mg, 428 umol) was separated by using chiral SFC (DAICEL CHIRALCEL OJ (250mm*30mm,10um); Supercritical CO2 / EtOH+0.1% NH3•H2O = 30/30; 70 mL/min) to afford (R)-2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (66 mg, first peak) as a white solid and (S)-2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (61 mg, second peak) as a white solid. Absolute configuration was arbitrarily assigned to each enantiomer. Compound 740: 1H NMR (400 MHz, DMSO-d6): δ 8.75 (s, 1H), 8.69 (s, 1H), 8.35 (d, J = 8.8 Hz, 1H), 7.86 - 7.79 (m, 1H), 7.75 (s, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.21 - 7.15 (m, 1H), 7.15 (s, 1H), 6.58 - 6.49 (m, 1H), 6.45 - 6.40 (m, 1H), 5.61 - 5.55 (m, 1H), 4.00 (s, 3H), 2.55 (s, 3H), 2.34 (s, 3H), 1.70 (d, J = 6.4 Hz, 3H). MS: m/z 468.1 (M+H+) Example 4: Preparation of 2-(((R)-1-(2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin- 1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 711) and 2-(((S)-1-(2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 712)
Figure imgf000267_0001
Step 1: Synthesis of tert-butyl 2-((1-(2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1- yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate To a solution of tert-butyl 2-((1-(2-hydroxy-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin- 9-yl)ethyl)amino)benzoate (120 mg, 0.31 mmol) in DMF (5 mL) was added PyBOP (189.5 mg, 0.36 mmol), DIEA (0.16 mL, 0.91 mmol). The mixture was stirred at room temperature for 30 min, cis-4,4-difluoro-3,5-dimethylpiperidine (90 mg, 0.61 mmol, prepared according to the procedure in WO2017125) was added. The reaction was stirred at 40 °C for 16 h. Water (10 mL) was added and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with aq. HCl (1 M, 80 mL), brine (80 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 20% EtOAc in petroleum ether) to give the title compound (80 mg, 50%) as a white solid.1H NMR (400 MHz, DMSO-d6): δ 8.56 (s, 1H), 8.19 (d, J = 5.6 Hz, 1H), 7.80 - 7.74 (m, 1H), 7.70 - 7.59 (m, 1H), 7.27 - 7.21 (m, 1H), 6.57 - 6.54 (m, 1H), 6.42 - 6.40 (m, 1H), 5.86 (s, 1H), 5.23 - 5.20 (m, 1H), 2.88 - 2.70 (m, 2H), 2.38 - 2.31 (m, 2H), 2.25 (s, 3H), 2.13 - 2.01 (m, 2H), 1.61 - 1.59 (m, 3H), 1.56 (s, 9H), 1.03 - 0.98 (m, 6H). MS: m/z 527.3 (M+H+). Step 2: Synthesis of 2-((1-(2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-7- methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid To a mixture of tert-butyl 2-((1-(2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-7- methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (140 mg, 0.26 mmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 16 h. This mixture was concentrated in vacuo and then diluted with MeOH (2 mL), then the mixture was adjusted pH to 10 with aq. LiOH (2 M), then adjusted pH to 6 with formic acid. The residue was purified by reverse phase chromatography (acetonitrile 65 - 95% / 0.225% formic acid in water) to give the title compound (80 mg, 63%) as a white solid. 1H NMR (400 MHz, DMSO- d6): δ 12.72 (s, 1H), 8.55 (s, 1H), 8.41 (d, J = 4.0 Hz, 1H), 7.81 (d, J = 4.0 Hz, 1H), 7.61 (s, 1H), 7.24 - 7.21 (m, 1H), 6.57 - 6.53 (m, 1H), 6.39 - 6.37 (m, 1H), 5.86 (s, 1H), 5.25 - 5.22 (m, 2H), 4.56 - 4.42 (m, 2H), 2.79 - 2.73 (m, 2H), 2.24 (s, 3H), 2.11 - 2.05 (m, 2H), 1.58 (d, J = 8.0 Hz, 3H), 1.02 - 0.99 (m, 6H). MS: m/z 471.2 (M+H+). Step 3: Synthesis of 2-(((R)-1-(2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-7- methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 711) and 2-(((S)-1-(2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 712) 2-((1-(2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (70 mg, 0.15 mmol) was separated by using chiral SFC (DAICEL CHIRALCEL OD-H (250mm*30mm,5um); Supercritical CO2 / EtOH + 0.1% NH3•H2O = 65/35; 60 ml/min) to afford 2-(((R)-1-(2-((3S,5R)-4,4-difluoro-3,5- dimethylpiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 711; 8 mg, first peak) and 2-(((S)-1-(2-((3S,5R)-4,4-difluoro-3,5- dimethylpiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 712; 10 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. Compound 711: 1H NMR (400 MHz, DMSO-d6): δ 8.55 (s, 1H), 7.82 (d, J = 4.0 Hz, 1H), 7.58 (s, 1H), 7.24 - 7.10 (m, 1H), 6.57 - 6.48 (m, 1H), 6.32 - 6.27 (m, 1H), 5.86 (s, 1H), 5.21 - 5.19 (m, 2H), 4.52 - 4.47 (m, 2H), 2.79 - 2.76 (m, 2H), 2.23 (s, 3H), 2.11 - 2.04 (m, 2H), 1.55 (d, J = 4.0 Hz, 3H), 1.02 - 0.99 (m, 6H). MS: m/z 471.6 (M+H+). Example 5: Preparation of 2-((1-(2-(4-fluorophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 691)
Figure imgf000269_0001
Step 1: Synthesis of 9-bromo-2-hydroxy-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one To a mixture of 3-bromo-5-methyl-pyridin-2-amine (12.3 g, 65.7 mmol) in acetone (200 mL) was heated to 40 °C for 0.5 h, and then bis(2,4,6-trichlorophenyl) 2-methylpropanedioate (34.5 g, 72.3 mmol) (prepared according to the procedure in Bioorg. Med. Chem. Lett., 2021, 47, 128208) was added dropwise at 40 °C. The final mixture was stirred at 65 °C for 4 h. After cooling to room temperature, the reaction mixture was filtrate to give the title compound (15 g, crude) as a yellow solid that required no further purification.1H NMR (400MHz, DMSO-d6): δ 11.66 (s, 1H), 8.71 (d, J = 1.6 Hz, 1H), 8.22 (d, J = 1.6 Hz, 1H), 2.34 (s, 3H), 1.96 (s, 3H). MS: m/z 268.8 (M+H+). Step 2: Synthesis of 2-(benzyloxy)-9-bromo-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4- one A mixture of 9-bromo-2-hydroxy-3,7-dimethyl-pyrido[1,2-a]pyrimidin-4-one (10 g, 37.2 mmol), K2CO3 (10.3 g, 74.3 mmol) and TBAI (1.37 g, 3.72 mmol) in DMF (100 mL) was added (bromomethyl)benzene (3.53 mL, 29.7 mmol). The mixture was stirred at 65 °C for 4 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was added water (1 L) and yellow solid was precipitated, filtrated. The residue was dissolve in ethyl acetate (1 L), washed with brine (500 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (12.7 g, crude) as a yellow solid that required no further purification.1H NMR (400MHz, DMSO-d6): δ 8.74 (d, J = 1.6 Hz,, 1H), 8.28 (s, J = 1.6 Hz, 1H), 7.53 (d, J = 7.2 Hz, 2H), 7.29-7.41 (m, 3H), 5.55 (s, 2H), 2.37 (s, 3H), 2.02 (s, 3H) MS: m/z 359.0 (M+H+). Step 3: Synthesis of 9-acetyl-2-(benzyloxy)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4- one A mixture of 2-(benzyloxy)-9-bromo-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (20 g, 55.7 mmol) and Pd(dppf)Cl2 (2.04 g, 2.78 mmol) in dioxane (200 mL) was degassed and purged with N2 for 3 times, and then tributyl(1-ethoxyvinyl)stannane (40.2 g, 111 mmol) was added, the final mixture was stirred at 90 °C for 16 h under N2 atmosphere. After cooling to room temperature, HCl (1 M, 20 mL) was added, the mixture was stirred at room temperature for 0.5 h. To the mixture was added 10% KF solution (300 mL), stirred at room temperature for 2 h. The mixture was filtered and extracted with EtOAc (300 mL x 3). The combined organic phase was washed with brine (200 mL x 2), dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified with silica gel chromatography (solvent gradient: 0 - 100% EtOAc in petroleum ether) to give the title compound (13.5 g, 75%) as a yellow solid.1H NMR (400MHz, DMSO-d6): δ 8.90 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.45 - 7.32 (m, 5H), 5.48 (s, 2H), 2.71 (s, 3H), 2.40 (s, 3H), 2.05 (s, 3H). MS: m/z 323.0 (M+H+). Step 4: Synthesis of 9-(1-aminoethyl)-2-(benzyloxy)-3,7-dimethyl-4H-pyrido[1,2- a]pyrimidin-4-one A mixture of 9-acetyl-2-benzyloxy-3,7-dimethyl-pyrido[1,2-a]pyrimidin-4-one (8 g, 24.8 mmol), NH4OAc (28.7 g, 372 mmol), NaBH3CN (4.68 g, 74.45 mmol) and AcOH (1.42 mL, 24.82 mmol) in MeOH (100 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 50 °C for 4 h under N2 atmosphere. After cooling to room temperature, MeOH (100 mL) was removed in vacuo, EtOAc (300 mL) was added, and the mixture was washed with sat. aq. NaHCO3 (200 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified silica gel chromatography (solvent gradient: 0 - 10% MeOH in DCM) to give the title compound (5 g, 62%) as yellow oil.1H NMR (400MHz, DMSO-d6): δ 8.69 (s, 1H), 7.92 (s, 1H), 7.46-7.44 (m, 2H), 7.40 - 7.36 (m, 2H), 7.32 - 7.29 (m, 1H), 5.52 (s, 2H), 4.68 - 4.63 (m, 3H),2.39 (s, 3H), 2.05 (s, 3H), 1.29 (d, J = 6.4 Hz, 3H). MS: m/z 324.4 (M+H+). Step 5: Synthesis of tert-butyl 2-((1-(2-(benzyloxy)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate A mixture of 9-(1-aminoethyl)-2-(benzyloxy)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin- 4-one (15.1 g, 46.7 mmol), tert-butyl 2-bromobenzoate (18.0 g, 70.0 mmol), Cs2CO3 (30.4 g, 93.4 mmol), Pd2(dba)3 (2.05 g, 2.24 mmol) and Xantphos (2.70 g, 4.67 mmol) in dioxane (200 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 16 h under N2 atmosphere. After cooling to room temperature, dioxane was removed in vacuo to give the crude residue. The crude residue was purified with silica gel chromatography (solvent gradient: 0 - 100% DCM in petroleum ether) to give the title compound (13.9 g, 60%) as yellow oil.1H NMR (400 MHz, DMSO-d6): δ 8.69 (s, 1H), 8.21 (d, J = 6.8 Hz, 1H), 7.78 - 7.72 (m, 1H), 7.47 (d, J = 7.2 Hz, 2H), 7.38 - 7.34 (m, 2H), 7.32-7.26 (m, 1H), 7.15 - 7.10 (m, 1H), 6.56 - 6.54 (m, 1H), 6.29 (d, J = 8.8 Hz, 1H), 5.63-5.60 (m, 2H), 5.31 - 5.28 (m, 1H), 2.31 (s, 3H), 2.08 (s, 3H), 1.56 (s, 9H), 1.52 (d, J = 6.4 Hz, 3H). MS: m/z 500.3 (M+H+). Step 6: Synthesis of tert-butyl 2-((1-(2-hydroxy-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate A mixture of tert-butyl 2-((1-(2-(benzyloxy)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (5 g, 10.0 mmol), Pd/C (2.72 g, 2.00 mmol, 10% purity) in MeOH (15 mL) was degassed and purged with H2 (15 psi) for 3 times, and then the mixture was stirred at room temperature for 1 h under H2 atmosphere. After the reaction was completed, the reaction mixture was filtrated. The filtrate was concentrated to give the tilte compound (4 g, crude) as a yellow solid that required no further purification. 1H NMR (400 MHz, DMSO-d6): δ 11.47 (s, 1H), 8.63 (s, 1H), 8.17 (d, J = 6.0 Hz, 1H), 7.78 – 7.76 (m, 1H), 7.60 (s, 1H), 7.22-7.18 (m, 1H), 6.57 – 6.53 (m, 1H), 6.27 (d, J = 8.4 Hz, 1H), 5.38 – 5.32 (m, 1H), 2.27 (s, 3H), 1.99 (s, 3H), 1.58 (s, 9H), 1.57 (d, J = 6.8 Hz, 3H). MS: m/z 410.2 (M+H+). Step 7: Synthesis of tert-butyl 2-((1-(3,7-dimethyl-4-oxo-2- (((trifluoromethyl)sulfonyl)oxy)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate To a solution of tert-butyl 2-((1-(2-hydroxy-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (0.6 g, 1.47 mmol) in DCM (15 mL) was added pyridine (355 uL, 4.40 mmol) and Tf2O (363 uL, 2.20 mmol).The mixture was stirred at 0 °C for 2 h. The mixture was diluted with DCM (50 mL), washed with 1M HCl (20 mL), brine (20 mL), dried over Na2SO4 and filtered. The filtrate was concentrated to give the crude which was purified with silica gel chromatography (solvent gradient: 0 - 10% EtOAc in petroleum ether) to give the title compound (0.72 g, 90%) as a yellow solid.1H NMR (400 MHz, DMSO-d6): δ 11.46 (s, 1H), 8.61 (s, 1H), 8.16 (d, J = 5.6 Hz, 1H), 7.77 (d, J = 6.4 Hz, 1H), 7.57 (s, 1H), 7.21 – 7.17 (m, 1H), 6.56 – 6.53 (m, 1H), 6.27 (d, J = 8.0 Hz, 1H), 5.36 – 5.33 (m, 1H), 2.26 (s, 3H), 1.98 (s, 3H), 1.59 (s, 9H), 1.56 (d, J = 6.4 Hz, 3H). MS: m/z 542.2 (M+H+). Step 8: Synthesis of tert-butyl 2-((1-(2-(4-fluorophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate To a solution of tert-butyl 2-((1-(3,7-dimethyl-4-oxo-2-(((trifluoromethyl)sulfonyl)oxy)- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (100 mg, 0.19 mmol), K2CO3 (77 mg, 0.55 mmol) and (4-fluorophenyl)boronic acid (78 mg, 0.55 mmol) in dioxane (3 mL) and water (1 mL) was added Pd(PPh3)4 (43 mg, 0.03 mmol). The reaction was stirred at 100 ºC for 2 h under N2 atmosphere. After cooling to room temperature, the reaction was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 5% MeOH in DCM) to give the title compound (50 mg, 56%) as yellow oil. MS: m/z 488.2 (M+H+). Step 9: Synthesis of 2-((1-(2-(4-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 721) To a solution of tert-butyl 2-((1-(2-(4-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (60 mg, 0.13 mmol) in DCM (3 mL) was added TFA(0.2 mL, 26 mmol). The reaction mixture was stirred at room temperature for 16 h. The solution was adjusted pH to 10 with aq. LiOH (2 M), then adjusted pH to 6 with formic acid. The crude residue was purified by reverse phase chromatography (acetonitrile 65-95% / 0.225% formic acid in water) to afford the title compound (15 mg, 28%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.61 (s, 1H), 7.82 - 7.79 (m, 3H), 7.66 (s, 1H), 7.39 - 7.34 (m, 2H), 7.16 - 7.13 (m, 1H), 6.53 - 6.52 (m, 1H), 6.32 (d, J = 8.4 Hz, 1H), 5.38 - 5.39 (m, 1H), 2.33 (s, 3H), 2.24 (s, 3H), 1.59 (d, J = 6.4 Hz, 3H). MS: m/z 432.0 (M+H+). Example 6: Preparation of (R)-2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzenesulfonamide (Compound 605) and (S)-2- ((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzenesulfonamide (Compound 606)
Figure imgf000273_0001
Step 1: Synthesis of 2-(benzyloxy)-9-(1-hydroxyethyl)-7-methyl-4H-pyrido[1,2- a]pyrimidin-4-one To a solution of 9-acetyl-2-benzyloxy-7-methyl-pyrido[1,2-a]pyrimidin-4-one (5 g, 16.2 mmol) in MeOH (50 mL) was added NaBH4 (950 mg, 25 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 h under N2 atmosphere. The mixture was quenched with sat. aq. NH4Cl (20 mL), diluted with water (20 mL), extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give the title compound (3.88 g, 77%) as a yellow solid. MS: m/z 311.2 (M+H+). Step 2: Synthesis of 2-(benzyloxy)-9-(1-bromoethyl)-7-methyl-4H-pyrido[1,2- a]pyrimidin-4-one To a solution of 2-benzyloxy-9-(1-hydroxyethyl)-7-methyl-pyrido[1,2-a]pyrimidin-4-one (3.88 g, 12.5 mmol) in DCM (40 mL) was added PBr3 (6.77 g, 25 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h under N2 atmosphere. The mixture was quenched with sat. aq. NaHCO3 (30 mL), extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give the title compound (2.25 g, 48%) as a yellow solid. MS: m/z 375.1 (M+2+H+). Step 3: Synthesis of 2-((1-(2-(benzyloxy)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzenesulfonamide To a solution of 2-benzyloxy-9-(1-bromoethyl)-7-methyl-pyrido[1,2-a]pyrimidin-4-one (500 mg, 1.34 mmol) in dioxane (6 mL) was added 2-aminobenzenesulfonamide (1.38 g, 8 mmol) at room temperature. The reaction was stirred at 100 ºC for 2 h under N2 atmosphere. After cooling to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 25% EtOAc in petroleum ether) to give the title compound (370 mg, 59%) as colorless oil.
Figure imgf000274_0001
NMR (400 MHz, DMSO-d6): δ 8.73 (s, 1H), 7.93 (d, J = 1.6 Hz, 1H), 7.64 (dd, J = 1.2, 8.0 Hz, 1H), 7.55 (s, 2H), 7.48 (d, J = 7.2 Hz, 2H), 7.40 - 7.35 (m, 2H), 7.33 - 7.29 (m, 1H), 7.24 - 7.19 (m, 2H), 7.15 (t, J = 7.6 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.68 - 6.57 (m, 2H), 6.43 (d, J = 6.0 Hz, 1H), 6.28 (d, J = 8.4 Hz, 1H), 5.83 (s, 1H), 5.52 (s, 2H), 5.33 (t, J = 6.4 Hz, 1H), 3.17 (d, J = 5.2 Hz, 2H), 2.30 (s, 3H), 1.52 (d, J = 6.4 Hz, 3H). MS: m/z 465.1 (M+H+). Step 4: Synthesis of 2-((1-(2-hydroxy-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzenesulfonamide: To a solution of 2-[1-(2-benzyloxy-7-methyl-4-oxo-pyrido[1,2-a]pyrimidin-9- yl)ethylamino]benzenesulfonamide (370 mg, 796 umol) in MeOH (5 mL) was added palladium on carbon (250 mg, 239 umol). The reaction was stirred at room temperature for 2 h under a hydrogen atmosphere. The reaction was filtrated and concentrated in vacuo to give the title compound (160 mg, crude) as a white solid. MS: m/z 375.1 (M+H+). Step 5: Synthesis of 2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzenesulfonamide To a solution of 2-[1-(2-hydroxy-7-methyl-4-oxo-pyrido[1,2-a]pyrimidin-9- yl)ethylamino]benzenesulfonamide (100 mg, 267 umol) in DMF (5 mL) was added PyBOP (167 mg, 320 umol), DIEA (0.23 mL, 1.34 mmol). The mixture was stirred at room temperature for 30 min, isoindoline (96 mg, 800 umol) was added. The reaction was stirred at 40 °C for 16 h. Water (10 mL) was added and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with aq. HCl (1 M, 100 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 50 - 80% / 0.225% formic acid in water) to give the title compound (100 mg, 78%) as a yellow solid. MS: m/z 476.0 (M+H+). Step 6: Synthesis of (R)-2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzenesulfonamide & (S)-2-((1-(2-(isoindolin-2-yl)-7-methyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzenesulfonamide 2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzenesulfonamide (100 mg, 0.21 mmol) was separated by using chiral SFC (DAICEL CHIRALCEL AD (250mm*30mm,10um); Supercritical CO2 / EtOH + 0.1% NH3•H2O = 35/65; 60 ml/min) to afford (R)-2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzenesulfonamide (Compound 605; 30 mg, first peak) and (S)-2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzenesulfonamide (Compound 606; 30 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. Compound 605: 1H NMR (400 MHz, DMSO-d6): δ 8.59 (s, 1H), 7.78 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.52 (s, 2H), 7.42 (d, J = 3.6 Hz, 2H), 7.35 - 7.31 (m, 2H), 7.23 (t, J = 7.6 Hz, 1H), 6.65 (t, J = 7.6 Hz, 1H), 6.48 - 6.44 (m, 2H), 5.44 (s, 1H), 5.42 - 5.38 (m, 1H), 5.00 (s, 2H), 4.74 (s, 2H), 2.25 (s, 3H), 1.64 (d, J = 6.4 Hz, 3H). MS: m/z 476.1 (M+H+). Example 7: Preparation of 2-(((R)-1-(2-((3aR,6aS)-5,5- difluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 582) and 2-(((S)-1-(2-((3aR,6aS)- 5,5-difluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 583)
Figure imgf000276_0001
Step 1: Synthesis of tert-butyl (3aR,6aS)-5,5-difluorohexahydrocyclopenta[c]pyrrole- 2(1H)-carboxylate To a solution of tert-butyl (3aR,6aS)-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)- carboxylate (500 mg, 2.22 mmol) in DCM (10 mL) was added DAST (1.43 g, 8.88 mmol) at 0 ºC. The reaction mixture was stirred at room temperature for 16 h under N2 atmosphere. The mixture was quenched with sat. aq. NaHCO3 (10 mL), diluted with water (20 mL), extracted with DCM (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 20% EtOAc in petroleum ether) to give the title compound (450 mg, 82%) as a yellow solid.1H NMR (400 MHz, DMSO-d6): δ 3.58 - 3.43 (m, 2H), 3.19 - 3.03 (m, 2H), 2.85 - 2.77 (m, 2H), 2.44 - 2.25 (m, 2H), 2.11 - 1.90 (m, 2H), 1.39 (s, 9H). Step 2: Synthesis of (3aR,6aS)-5,5-difluorooctahydrocyclopenta[c]pyrrole trifluoroacetate To a solution of tert-butyl (3aR,6aS)-5,5-difluorohexahydrocyclopenta[c]pyrrole-2(1H)- carboxylate (450 mg, 1.82 mmol) in DCM (10 mL) was added TFA (1.04 g, 9 mmol). The reaction mixture was stirred at room temperature for 2 h under N2 atmosphere. The mixture was concentrated in vacuo to give the title compound (450 mg, 82%) as a yellow oil.1H NMR (400 MHz, DMSO-d6): δ 3.56 - 3.42 (m, 2H), 2.76 - 2.72 (m, 2H), 2.62 - 2.55 (m, 2H), 2.30 - 2.13 (m, 2H), 1.92 - 1.71 (m, 2H). Step 3: Synthesis of tert-butyl 2-((1-(2-((3aR,6aS)-5,5-difluorohexahydrocyclopenta[c] pyrrol-2(1H)-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate To a solution of tert-butyl 2-[1-(2-hydroxy-7-methyl-4-oxo-pyrido[1,2-a]pyrimidin-9- yl)ethylamino]benzoate (180 mg, 45 umol) in DMF (5 mL) was added PyBOP (280 mg, 543 umol), DIEA (0.24 mL, 1.81 mmol). The mixture was stirred at room temperature for 30 min, (3aR,6aS)-5,5-difluorooctahydrocyclopenta[c]pyrrole trifluoroacetate (200 mg, 1.36 mmol) was added. The reaction was stirred at 40 °C for 16 h. Water (10 mL) was added and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with aq. HCl (1 M, 100 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give the title compound (120 mg, 50%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.55 (s, 1H), 8.21 (d, J = 6.4 Hz, 1H), 7.76 (d, J = 5.6, 1H), 7.62 (s, 1H), 7.24 ( t, J = 7.6 Hz, 1H), 6.55 (t, J = 7.2 Hz, 1H), 6.44 (d, J = 8.4 Hz, 1H), 5.31 (s, 1H), 5.23 (q, J = 6.8 Hz, 1H), 3.95 - 3.65 (m, 2H), 3.57 - 3.41 (m, 2H), 3.18 - 3.15 (m, 1H), 3.01 - 2.96 ( s, 2H), 2.46 - 2.36 (m, 2H), 2.24 (s, 3H), 2.19 - 1.99 (m, 2H), 1.62 (d, J = 6.8 Hz, 3H), 1.56 (s, 9H). MS: m/z 525.3 (M+H+). Step 4: 2-((1-(2-((3aR,6aS)-5,5-difluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-7- methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid To a mixture of tert-butyl 2-((1-(2-((3aR,6aS)-5,5-difluorohexahydrocyclopenta[c]pyrrol- 2(1H)-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (120 mg, 228 umol) in DCM (3 mL) was added TFA (1 mL). The reaction was stirred at room temperature for 16 h. This mixture was concentrated in vacuo and then dulited with MeOH (2mL). The mixture was adjusted pH to 10 with aq. LiOH (2 M), then adjusted pH to 6 with formic acid. The residue was purified by reverse phase chromatography (acetonitrile 10-33% / 0.225% formic acid in water) to give the title compound (40 mg, 37%) as a white solid.1H NMR (400 MHz, DMSO- d6): δ 12.72 (s, 1H), 8.54 (s, 1H), 8.47 (s, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 1.6 Hz, 1H), 7.22 - 7.20 (m, 1H), 6.53 (t, J = 7.2 Hz, 1H), 6.36 (d, J = 8.4 Hz, 1H), 5.31 (s, 1H), 5.27 - 5.15 (m, 1H), 3.91 - 3.64 (m, 2H), 3.54 - 3.39 (m, 2H), 2.96 (s, 2H), 2.44 - 2.36 (m, 2H), 2.23 (s, 3H), 2.17 - 2.04 (m, 2H), 1.59 (d, J = 6.4 Hz, 3H). MS: m/z 469.0 (M+H+). Step 5: Synthesis of 2-(((R)-1-(2-((3aR,6aS)-5,5-difluorohexahydrocyclopenta[c]pyrrol- 2(1H)-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 582) and 2-(((S)-1-(2-((3aR,6aS)-5,5-difluorohexahydrocyclopenta[c]pyrrol-2(1H)- yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 583) 2-((1-(2-((3aR,6aS)-5,5-difluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-7-methyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (40 mg, 85 umol) was separated by using chiral SFC (DAICEL CHIRALCEL OJ (250mm*30mm,10um); Supercritical CO2 / EtOH + 0.1% NH3•H2O = 30/70; 60 ml/min) to afford 2-(((R)-1-(2-((3aR,6aS)-5,5- difluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (15 mg, first peak) and 2-(((S)-1-(2-((3aR,6aS)-5,5- difluorohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (11 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. Compound 583: 1H NMR (400 MHz, DMSO-d6): δ 12.70 (s, 1H), 8.54 (s, 1H), 8.50 (s, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.58 (d, J = 1.6 Hz, 1H), 7.22 - 7.20 (m, 1H), 6.54 - 6.52 (m, 1H), 6.36 (d, J = 8.4 Hz, 1H), 5.31 (s, 1H), 5.27 - 5.15 (m, 1H), 3.91 - 3.64 (m, 2H), 3.54 - 3.39 (m, 2H), 2.96 (s, 2H), 2.44 - 2.36 (m, 2H), 2.23 (s, 3H), 2.17 - 2.04 (m, 2H), 1.59 (d, J = 6.4 Hz, 3H). MS: m/z 469.0 (M+H+). Example 8: Preparation of (S)-2-((1-(2-(3-amino-1-methyl-1H-indazol-5-yl)-7- methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 536)
Figure imgf000278_0001
Step 1: Synthesis of tert-butyl 2-((1-(2-(3-amino-1-methyl-1H-indazol-5-yl)-7-methyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate To a solution of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-3- amine (155 mg, 569 umol, prepared according to the procedure in WO2015140054), tert-butyl 2- [1-[7-methyl-4-oxo-2-(trifluoromethylsulfonyloxy)pyrido[1,2-a]pyrimidin-9- yl]ethylamino]benzoate (150 mg, 284 umol), K2CO3 (118 mg, 853 umol) in dioxane (2 mL) and water (0.2 mL) was added Pd(PPh3)4 (33 mg, 28 umol). The reaction mixture was stirred at 100 °C for 2 h under N2 atmosphere. After cooling to room temperature, EtOAc (30 mL) was added, and the mixture was washed with brine (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give the title compound (125 mg, 84%) as a brown solid. MS: m/z 525.1 (M+H+). Step 2: Synthesis of tert-butyl (R)-2-((1-(2-(3-amino-1-methyl-1H-indazol-5-yl)-7- methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate & tert-butyl (S)-2-((1-(2- (3-amino-1-methyl-1H-indazol-5-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoate tert-butyl 2-((1-(2-(3-amino-1-methyl-1H-indazol-5-yl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (125 mg, 238 umol) was separated by using chiral SFC (DAICEL CHIRALCEL OD-H (250 mm*30 mm,5 um); Supercritical CO2 / EtOH + 0.1% NH3•H2O = 65/35; 60 ml/min) to afford tert-butyl (R)-2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)- 7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (60 mg, first peak) and tert-butyl (S)-2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (60 mg, second peak) both as yellow solid. Absolute configuration was arbitrarily assigned to each enantiomer. Step 3: Synthesis of (S)-2-((1-(2-(3-amino-1-methyl-1H-indazol-5-yl)-7-methyl-4-oxo- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 536) To a mixture of tert-butyl (S)-2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-7-methyl-4-oxo- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (60 mg, 114 umol) in DCM (3 mL) was added TFA (1 mL). The reaction was stirred at room temperature for 16 h. This mixture was concentrated in vacuo and then diluted with MeOH (2 mL). The solution was adjusted pH to 10 with aq. LiOH (2 M), then adjusted pH to 6 with formic acid. The solution was purified by reverse phase chromatography (acetonitrile 3-33% / 0.225% formic acid in water) to give the title compound (Compound 536; 18 mg, 33%) as a yellow solid.1H NMR (400 MHz, DMSO- d6): δ 8.76 (s, 1H), 8.72 (s, 1H), 8.67 - 8.57 (m, 1H), 8.23 - 8.21 (m, 1H), 7.83 - 7.81 (m, 1H), 7.73 - 7.72 (m, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.19 - 7.15 (m, 1H), 6.95 (s, 1H), 6.53 (t, J = 7.6 Hz, 1H), 6.40 (d, J = 8.4 Hz, 1H), 5.63 (s, 1H), 3.77 (s, 3H), 2.33 (s, 3H), 1.68 (d, J = 6.4 Hz, 3H). MS: m/z 468.5 (M+H+). Example 9: Preparation of rel-(R)-2-((1-(2-(3-amino-1-methyl-1H-indazol-5-yl)-7- methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 535) and rel-(R)-2-((1-(2-(3-amino-1-methyl-1H-indazol-5-yl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 536)
Figure imgf000280_0001
2-({1-[2-(3-amino-1-methylindazol-5-yl)-7-methyl-4-oxopyrido[1,2-a]pyrimidin-9- yl]ethyl}amino)benzoic acid (100 mg, 0.213 mmol, 1 equiv) was isolated by prep-chiral-HPLC with the following conditions : Column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.1% FA)--HPLC, Mobile Phase B: EtOH--HPLC; Flow rate: 20 mL/min; Gradient: 30% B to 30% B (isocratic) in 18 min; Wave Length: 220/203 nm; RT1(min): 9.69; RT2(min): 14.55; Sample Solvent: HFIP; Injection Volume: 0.5 mL; Number Of Runs: 8. The 1st eluting fraction was concentrated under vacuum and lyophilized to afford rel-(R)-2-((1-(2-(3- amino-1-methyl-1H-indazol-5-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (Compound 535; 26.3 mg, 25.98%) as an yellow solid. The 2nd eluting fraction was concentrated under vacuum and lyophilized to afford rel-(R)-2-((1-(2-(3- amino-1-methyl-1H-indazol-5-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (Compound 536; 13.4 mg, 13.28%) as a yellow solid. Compound 535: 1H NMR (400 MHz, DMSO-d6) δ 8.98 – 8.72 (m, 2H), 8.71 – 8.33 (m, 1H), 8.23 (dd, J = 8.9, 1.6 Hz, 1H), 7.84 (dd, J = 8.0, 1.7 Hz, 1H), 7.73 (d, J = 2.0 Hz, 1H), 7.44 (d, J = 9.0 Hz, 1H), 7.20 (ddd, J = 8.7, 7.1, 1.7 Hz, 1H), 6.97 (s, 1H), 6.55 (ddd, J = 8.1, 7.1, 1.0 Hz, 1H), 6.43 (d, J = 8.5 Hz, 1H), 5.66 (s, 1H), 3.78 (s, 3H), 2.33 (d, J = 1.2 Hz, 3H), 1.70 (d, J = 6.6 Hz, 3H). LC-MS: (ES+H, m/z): [M+H]+ = 469.2. Compound 536: 1H NMR (400 MHz, DMSO-d6) δ 8.91 – 8.68 (m, 2H), 8.52 (s, 1H), 8.23 (dd, J = 8.9, 1.7 Hz, 1H), 7.83 (dd, J = 8.0, 1.8 Hz, 1H), 7.73 (d, J = 2.1 Hz, 1H), 7.44 (d, J = 8.9 Hz, 1H), 7.20 (ddd, J = 8.7, 7.1, 1.8 Hz, 1H), 6.96 (s, 1H), 6.55 (t, J = 7.5 Hz, 1H), 6.43 (d, J = 8.5 Hz, 1H), 5.65 (s, 1H), 3.78 (s, 3H), 2.44 – 2.22 (m, 3H), 1.70 (d, J = 6.5 Hz, 3H). LC-MS: (ES+H, m/z): [M+H]+ = 469.2. Example 10: Preparation of rel-2-{[(1R)-1-[7-methyl-4-oxo-2-(pyridin-4- yl)pyrido[1,2-a]pyrimidin-9-yl]ethyl]amino}benzamide (Compound 439) and rel-2-{[(1R)- 1-[7-methyl-4-oxo-2-(pyridin-4-yl)pyrido[1,2-a]pyrimidin-9-yl]ethyl]amino}benzamide (Compound 440)
Figure imgf000281_0001
2-({1-[7-methyl-4-oxo-2-(pyridin-4-yl)pyrido[1,2-a]pyrimidin-9- yl]ethyl}amino)benzamide (76 mg, 0.190 mmol, 1 equiv) was isolated by Prep-CHIRAL-HPLC with the following conditions: Column: CHIRAL ART Cellulose-SZ, 3*25 cm, 5 μm; Mobile Phase A: Hex(10mM NH3-MeOH), Mobile Phase B: EtOH--HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B (isocratic)in 37 min; Wave Length: 206/256 nm; RT1(min): 18.85; RT2(min): 26.65; Sample Solvent: MeOH: DCM=1: 2; Injection Volume: 0.7 mL; Number Of Runs: 5; The 1st eluting fraction was concentrated under reduced pressure to afford rel-2-{[(1R)- 1-[7-methyl-4-oxo-2-(pyridin-4-yl)pyrido[1,2-a]pyrimidin-9-yl]ethyl]amino}benzamide (Compound 439; 26.9 mg, 35.39%,ee=100%) as a white solid. The 2nd eluting fraction was concentrated under reduced pressure to afford rel-2-{[(1R)-1-[7-methyl-4-oxo-2-(pyridin-4- yl)pyrido[1,2-a]pyrimidin-9-yl]ethyl]amino}benzamide (Compound 440; 34.1 mg, 44.87%, ee=99.59%) as a white solid. Compound 439: 1H NMR (300 MHz, DMSO-d6) δ 8.85 (d, J = 6.4 Hz, 1H), 8.81 – 8.75 (m, 3H), 8.25 – 8.20 (m, 2H), 7.93 (s, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.67-7.61(m, 1H), 7.28 (s, 1H), 7.21 (s, 1H), 7.15 – 7.06 (m, 1H), 6.56-6.43(m, 1H), 6.36 (d, J = 8.4 Hz, 1H), 5.56-5.44(m, 1H), 2.40 – 2.31 (m, 3H), 1.64 (d, J = 6.6 Hz, 3H). LC-MS: (ES+H, m/z): [M+H]+ = 400.1 Compound 440: 1H NMR (300 MHz, DMSO-d6) δ 8.85 (d, J = 6.3 Hz, 1H), 8.81 – 8.72 (m, 3H), 8.25 – 8.20 (m, 2H), 7.93 (s, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.67-7.61(m, 1H), 7.28 (s, 1H), 7.21 (d, J = 2.0 Hz, 1H), 7.15 – 7.06 (m, 1H), 6.56-6.43(m, 1H), 6.36 (d, J = 8.4 Hz, 1H), 5.56-5.44(m, 1H), 2.40 – 2.31 (m, 3H), 1.64 (d, J = 6.5 Hz, 3H). LC-MS: (ES+H, m/z): [M+H]+ = 400.1 Example 11: Preparation of 2-((1-(7-methyl-2-(7-methyl-2-oxo-2,3- dihydrobenzo[d]oxazol-5-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 1413)
Figure imgf000282_0001
Step 1: Synthesis of 7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzo[d]oxazol-2(3H)-one To a solution of 5-chloro-7-methyl-3H-1,3-benzoxazol-2-one (0.3 g, 1.63 mmol) (prepared according to the procedure in US2015210655) and 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (830 mg, 3.27 mmol) in dioxane (10 mL) was added Xphos-Pd-G2 (128 mg, 163 umol) and KOAc (401 mg, 4.09 mmol). The reaction mixture was stirred at 110 °C for 2 hours under N2 atmosphere. After cooling to room temperature, the reaction was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give 7- methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one (200 mg, 45%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 7.44 (s, 1H), 7.33 (s, 1H), 2.39 (s, 3H), 1.35 (s, 12H). MS: m/z 276.1 (M+H+). Step 2 - Synthesis of tert-butyl 2-((1-(7-methyl-2-(7-methyl-2-oxo-2,3- dihydrobenzo[d]oxazol-5-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate To a solution of tert-butyl 2-((1-(7-methyl-4-oxo-2-(((trifluoromethyl)sulfonyl)oxy)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (70 mg, 132 umol) and 7-methyl-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one (73 mg, 265 umol) in dioxane (6 mL) and water (1.5 mL) was added Pd(PPh3)4 (15 mg, 13 umol) and K2CO3 (55 mg, 398 umol). The mixture was stirred at 100 °C for 4 h under N2 atmosphere. After cooling to room temperature, the reaction was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to tert-butyl 2-((1-(7- methyl-2-(7-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin- 9-yl)ethyl)amino)benzoate (40 mg, 58%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.76 (s, 1H), 8.75 (s, 1H), 8.34 (d, J = 4.8 Hz, 1H), 7.90 (s, 1H), 7.82 - 7.80 (m, 2H), 7.77 (d, J = 8.0 Hz, 1H), 7.21 (t, J = 7.2 Hz, 1H), 7.02 (s, 1H), 6.55 (t, J = 7.6 Hz, 1H), 6.46 ( d, J = 8.4 Hz, 1H), 5.57 - 5.44 (m, 1H), 2.40 (s, 3H), 2.35 (s, 3H), 1.70 (d, J = 6.4 Hz, 3H), 1.53 (s, 9H). MS: m/z 527.2 (M+H+). Step 3 - Synthesis of 2-((1-(7-methyl-2-(7-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol- 5-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 319) To a mixture of tert-butyl 2-((1-(7-methyl-2-(7-methyl-2-oxo-2,3- dihydrobenzo[d]oxazol-5-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (30 mg, 57 umol) in DCM (1.5 mL) was added TFA (0.5 mL). The reaction mixture was stirred at room temperature for 5 hours. The mixture was concentrated in vacuo. The residue was adjusted pH to 6 with NH3•H2O (25% w/w) solution. The resulting mixture was purified by Prep-TLC (10% MeOH in DCM) to give 2-((1-(7-methyl-2-(7-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5- yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (7 mg, 23%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 12.72 (s, 1H), 11.73 (s, 1H), 8.74 (s, 1H), 8.53 (s, 1H), 7.90 (s, 1H), 7.85 - 7.75 (m, 3H), 7.20 (t, J = 8.0 Hz, 1H), 7.03 (s, 1H), 6.55 (t, J = 7.6 Hz, 1H), 6.41 (d, J = 8.4 Hz, 1H), 5.58 - 5.49 (m, 1H), 2.40 (s, 3H), 2.34 (s, 3H), 1.67 (d, J = 6.4 Hz, 3H). MS: m/z 471.2 (M+H+). Example 12: Preparation of (S)-2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 393)
Figure imgf000283_0001
Step 1 - tert-butyl 2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate To a solution of tert-butyl 2-((1-(2-hydroxy-7-methyl- 4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (150 mg, 379 umol) in DMF (2 mL) was added DIEA (198 uL, 1.14 mmol) and PyBOP (236 mg, 455 umol). The reaction mixture was stirred at room temperature for 10 minutes, then isoindoline (135 mg, 1.14 mmol) was added. The reaction mixture was stirred at 40 °C for 16 hours. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with aq. HCl (1 M, 30 mL) and brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give tert- butyl 2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoate (150 mg, 79%) as a white solid. MS: m/z 497.2 (M+H+). Step 2 - Synthesis of 2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid To a solution of tert-butyl 2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (150 mg, 302 umol) in DCM (3 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo. The residue was purified by Prep-TLC (10% MeOH in DCM) to give 2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (100 mg, 68%) as a yellow solid. MS: m/z 441.2 (M+H+). Step 3 - (R)-2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid & (S)-2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 403) 2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (100 mg, 227 umol) was separated by using chiral SFC (DAICEL CHIRALCEL OJ-H (250mm*30mm,5um); Supercritical CO2 / EtOH + 0.1% NH3•H2O = 70/30; 60 ml/min) to afford (R)-2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin- 9-yl)ethyl)amino)benzoic acid (41 mg, first peak) and (S)-2-((1-(2-(isoindolin-2-yl)-7-methyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (34 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. Compound 403: 1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 2H), 7.80 (dd, J = 8.0, 1.6 Hz, 1H), 7.64 (d, J =1.6 Hz, 1H), 7.44 - 7.40 (m, 2H), 7.35 - 7.29 (m, 2H), 7.23 (t, J = 7.2 Hz, 1H), 6.53 (t, J = 7.2 Hz, 1H), 6.47 (d, J = 8.8 Hz, 1H), 5.42 (s, 1H), 5.38 - 5.31 (m, 1H), 5.11 - 4.86 (m, 2H), 4.78 - 4.68 (m, 2H), 2.25 (s, 3H), 1.66 (d, J = 6.8 Hz, 3H). MS: m/z 441.1 (M+H+). Example 13: Preparation of (R)-2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzamide (Compound 620)
Figure imgf000285_0001
Step 1 - Synthesis of 9-bromo-2-(isoindolin-2-yl)-7-methyl-4H-pyrido[1,2- a]pyrimidin-4-one: To a solution of 9-bromo-2-hydroxy-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (5 g, 20 mmol) in DMF (100 mL) was added PyBOP (12 g, 23 mmol) and DIEA (10.2 mL, 59 mmol). The mixture was stirred at room temperature for 20 minutes, isoindoline hydrochloride (4.7 g, 30 mmol) was added. The reaction was stirred at 40 °C for 16 hours. After cooling to room temperature, the reaction was quenched with water (100 mL), and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with aq. HCl (1 M, 200 mL), brine (200 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 20% EtOAc in petroleum ether) to give 9- bromo-2-(isoindolin-2-yl)-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (6.5 g, 93%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J = 1.6 Hz, 1H), 8.22 (d, J = 1.6 Hz, 1H), 7.49 - 7.41 (m, 2H), 7.36 - 7.32 (m, 2H), 5.42 (s, 1H), 4.99 - 4.92 (m, 2H), 4.78 - 4.69 (m, 2H), 2.25 (s, 3H). MS: m/z 358.0 (M+H+). Step 2 - Synthesis of 9-(1-ethoxyvinyl)-2-(isoindolin-2-yl)-7-methyl-4H-pyrido[1,2- a]pyrimidin-4-one: A mixture of 9-bromo-2-(isoindolin-2-yl)-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (6.5 g, 18 mmol), tributyl(1-ethoxyvinyl)stannane (14 g, 39 mmol), Pd(dppf)Cl2 (668 mg, 912 umol) in dioxane (100 mL) was stirred at 100 °C for 16 h under N2 atmosphere. After cooling to room temperature, the mixture was quenched with 100 mL of 10% KF aqueous solution, stirred for 30 min. The mixture was extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 5% MeOH in DCM) to give 9-(1-ethoxyvinyl)-2-(isoindolin-2-yl)-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (4.1 g, 64%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 7.94 (d, J = 2.4 Hz, 1H), 7.45 - 7.41 (m, 2H), 7.37 - 7.30 (m, 2H), 5.65 (s, 1H), 5.42 (s, 1H), 4.89 (s, 2H), 4.80 (s, 1H), 4.72 (s, 2H), 3.96 (q, J = 6.8 Hz, 2H), 2.34 (s, 3H), 1.37 (t, J = 6.8 Hz, 3H). MS: m/z 348.2 (M+H+). Step 3 - Synthesis of 9-acetyl-2-(isoindolin-2-yl)-7-methyl-4H-pyrido[1,2- a]pyrimidin-4-one To a solution of 9-(1-ethoxyvinyl)-2-(isoindolin-2-yl)-7-methyl-4H-pyrido[1,2- a]pyrimidin-4-one (1 g, 2.88 mmol) in THF (10 mL) was added 1M HCl (5 mL). The reaction mixture was stirred at room temperature for 3 hours. The mixture was adjusted to pH 7 with sat. aq. NaHCO3, then extracted with EtOAc (60 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to give 9-acetyl-2- (isoindolin-2-yl)-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.9 g, crude) as a brown solid that required no further purification.1H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.49 - 7.38 (m, 2H), 7.37 - 7.30 (m, 2H), 5.43 (s, 1H), 4.93 (s, 2H), 4.73 (s, 2H), 2.84 (s, 3H), 2.35 (s, 3H). Step 4 - Synthesis of 9-(1-hydroxyethyl)-2-(isoindolin-2-yl)-7-methyl-4H-pyrido[1,2- a]pyrimidin-4-one To a solution of 9-acetyl-2-(isoindolin-2-yl)-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (1 g, 3.13 mmol) in MeOH (20 mL) was added NaBH4 (142 mg, 3.76 mmol) at 0 °C. The mixture was stirred at room temperature for 16 hours under N2 atmosphere. The mixture was quenched with 1M HCl (10 mL) at 0 °C, diluted with water (20 mL), extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give 9-(1- hydroxyethyl)-2-(isoindolin-2-yl)-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.97 g, 96%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.42 (s, 2H), 7.35 - 7.29 (m, 2H), 5.42 - 5.27 (m, 3H), 4.99 - 4.65 (m, 4H), 2.33 (s, 3H), 1.47 (d, J = 6.4 Hz, 3H). MS: m/z 322.2 (M+H+). Step 5 - Synthesis of 9-(1-bromoethyl)-2-(isoindolin-2-yl)-7-methyl-4H-pyrido[1,2- a]pyrimidin-4-one To a solution of 9-(1-hydroxyethyl)-2-(isoindolin-2-yl)-7-methyl-4H-pyrido[1,2- a]pyrimidin-4-one (957 mg, 2.98 mmol) in DCM (10 mL) was added PBr3 (1.6 g, 5.91 mmol) at 0 °C. The mixture was stirred at room temperature for 16 hours under N2 atmosphere. The mixture was quenched with sat. aq. NaHCO3 (30 mL), extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give 9-(1-bromoethyl)-2-(isoindolin-2-yl)-7- methyl-4H-pyrido[1,2-a]pyrimidin-4-one (455 mg, 40%) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 7.76 (d, J = 2.0 Hz, 1H), 7.41 - 7.32 (m, 4H), 6.16 - 6.09 (m, 1H), 5.58 (s, 1H), 5.19 - 4.95 (m, 2H), 4.75 - 4.68 (m, 2H), 2.39 (s, 3H), 2.14 (d, J = 6.8 Hz, 3H). Step 6 - Synthesis of 2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzamide A mixture of 9-(1-bromoethyl)-2-(isoindolin-2-yl)-7-methyl-4H-pyrido[1,2-a]pyrimidin- 4-one (100 mg, 260 umol) and 2-aminobenzamide (71 mg, 520 umol) in dioxane (1 mL) was stirred at 100 °C for 2 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 55% - 85% / 0.225% formic acid in water) to give 2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzamide (30 mg, 26%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J = 6.8 Hz, 1H), 8.58 (s, 1H), 7.88 (s, 1H), 7.64 - 7.57 (m, 2H), 7.45 - 7.41 (m, 2H), 7.36 - 7.30 (m, 2H), 7.23 (s, 1H), 7.16 - 7.12 (m, 1H), 6.53 - 6.49 (m, 1H), 6.39 (d, J = 8.4 Hz, 1H), 5.43 (s, 1H), 5.36 - 5.25 (m, 1H), 5.12 - 4.87 (m, 2H), 4.76 - 4.70 (m, 2H), 2.25 (s, 3H), 1.61 (d, J = 6.8 Hz, 3H). MS: m/z 440.2 (M+H+). Step 7 - Synthesis of (R)-2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzamide (Compound 37) & (S)-2-((1-(2-(isoindolin-2-yl)-7- methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzamide 2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzamide (20 mg, 45 umol) was separated by using chiral SFC (DAICEL CHIRALCEL AD (250mm*30mm,10um); Supercritical CO2 / EtOH+0.1% NH3•H2O = 55/45; 60 mL/min) to afford (R)-2-((1-(2-(isoindolin-2-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin- 9-yl)ethyl)amino)benzamide (7 mg, first peak) and (S)-2-((1-(2-(isoindolin-2-yl)-7-methyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzamide (5 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. Compound 646: 1H NMR (400 MHz, DMSO-d6) δ 8.79 (d, J = 6.4 Hz, 1H), 8.58 (s, 1H), 7.89 (s, 1H), 7.63 - 7.58 (m, 2H), 7.46 - 7.40 (m, 2H), 7.36 - 7.30 (m, 2H), 7.23 (s, 1H), 7.15 - 7.11 (m, 1H), 6.52 - 6.48 (m, 1H), 6.39 (d, J = 8.4 Hz, 1H), 5.43 (s, 1H), 5.33 - 5.27 (m, 1H), 5.09 - 4.88 (m, 2H), 4.78 - 4.68 (m, 2H), 2.25 (s, 3H), 1.61 (d, J = 6.4 Hz, 3H). MS: m/z 440.1 (M+H+). Example 14: Preparation of 2-((1-(7-methyl-4-oxo-2-(pyridin-3-yl)-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid trifluoroacetate (Compound 416)
Figure imgf000288_0001
Step 1 - Synthesis of tert-butyl 2-((1-(7-methyl-4-oxo-2-(pyridin-3-yl)-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate A mixture of tert-butyl 2-((1-(7-methyl-4-oxo-2-(((trifluoromethyl)sulfonyl)oxy)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (150 mg, 284 umol), 3-pyridylboronic acid (87 mg, 711 umol), Pd(PPh3)4 (66 mg, 57 umol), K2CO3 (118 mg, 853 umol) in dioxane (1.5 mL) and water (0.15 mL) was stirred at 100 °C for 2 hours under N2 atmosphere. After cooling to room temperature, the reaction mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give tert-butyl 2-((1-(7-methyl-4-oxo-2-(pyridin-3-yl)-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (100 mg, 77%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.79 (s, 1H), 8.72 (d, J = 4.0 Hz, 1H), 8.63 (d, J = 8.0 Hz, 1H), 8.36 (d, J = 6.0 Hz, 1H), 7.85 (s, 1H), 7.74 - 7.79 (m, 1H), 7.22 - 7.18 (m, 1H), 7.16 (s, 1H), 6.57 - 7.53 (m, 1H), 6.49 (d, J = 8.4 Hz, 1H), 5.55 - 5.49 (m, 1H), 2.37 (s, 3H), 1.71 (d, J = 6.8 Hz, 3H), 1.53 (s, 9H). MS: m/z 457.1 (M+H+). Step 2 - Synthesis of 2-((1-(7-methyl-4-oxo-2-(pyridin-3-yl)-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid trifluoroacetate To a solution of tert-butyl 2-((1-(7-methyl-4-oxo-2-(pyridin-3-yl)-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (100 mg, 219 umol) in DCM (1.5 mL) was added TFA (0.5 mL). The mixture was stirred at 40 °C for 16 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The resulting residue was purified by reverse phase chromatography (acetonitrile 27% - 57% / 0.225% formic acid in water) to give 2-((1-(7-methyl- 4-oxo-2-(pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid trifluoroacetate (Compound 426) (70 mg, 80%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 12.75 (s, 1H), 9.45 (d, J = 1.6 Hz, 1H), 8.78 (s, 1H), 8.72 (d, J = 4.0 Hz, 1H), 8.63 (d, J = 8.0 Hz, 1H), 8.51 (d, J = 6.4 Hz, 1H), 7.79 - 7.83 (m, 2H), 7.58 (dd, J = 8.0, 4.8 Hz, 1H), 7.17 - 7.23 (m, 1H), 7.17 (s, 1H), 6.57 - 6.53 (m, 1H), 6.44 (d, J = 8.4 Hz, 1H), 5.58 - 5.52 (m, 1H), 2.36 (s, 3H), 1.68 (d, J = 6.4 Hz, 3H). MS: m/z 401.0 (M+H+). Example 15: Preparation of 2-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid trifluoroacetate (Compound 1412)
Figure imgf000289_0001
Step 1 - Synthesis of tert-butyl 2-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate To a solution of tert-butyl 2-((1-(2-hydroxy-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (150 mg, 366 umol) in DMF (3 mL) was added DIEA (447 uL, 2.56 mmol) and PyBOP (248 mg, 476 umol). The mixture was stirred at room temperature for 20 min, isoindoline hydrochloride (257 mg, 1.65 mmol) was added. The final mixture was stirred at 50 ℃ for 16 hours. After cooling to room temperature, the reaction mixture was poured into 1M aq. HCl (30 mL). The suspension solution was filtered, the filter cake was dissolved in EtOAc (100 mL). The mixture was washed with brine (30 mL), dried over anhydrous Na2SO4, concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give tert-butyl 2-((1-(2- (isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (110 mg, 32%) as a white solid. MS: m/z 511.2 (M+H+). Step 2 - Synthesis of 2-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid trifluoroacetate (Compound 764) To a solution of tert-butyl 2-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (30 mg, 59 umol) in DCM (1.5 mL) was added TFA (0.5 ml). The mixture was stirred at 40 °C for 16 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The resulting residue was purified by reverse phase chromatography (acetonitrile 54% - 84% / 0.225% formic acid in water) to give 2-((1-(2- (isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid trifluoroacetate (Compound 764) (11 mg, 41%) as a yellow solid. 1H NMR (400 MHz, DMSO- d6) δ 12.73 (s, 1H), 8.56 (s, 1H), 8.43 (d, J = 5.6 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.53 - 7.59 (m, 1H), 7.36 - 7.43 (m, 2H), 7.27 - 7.34 (m, 2H), 7.26 - 7.20 (m, 1H), 6.56 - 6.52 (m, 1H), 6.41 (d, J = 8.0 Hz, 1H), 5.38 - 5.32 (m, 1H), 5.23 - 5.13 (m, 4H), 2.42 (s, 3H), 2.26 (s, 3H), 1.64 (d, J = 6.4 Hz, 3H). MS: m/z 455.0 (M+H+). Example 16: Preparation of (R)-2-((1-(2-(4,4-dimethyl-1,4-azasilinan-1-yl)-7-methyl- 4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 431)
Figure imgf000290_0001
Step 1 - Synthesis of tert-butyl 2-((1-(2-(4,4-dimethyl-1,4-azasilinan-1-yl)-7-methyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate To a solution of tert-butyl 2-((1-(2-hydroxy-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin- 9-yl)ethyl)amino)benzoate (200 mg, 506 umol) in DMF (4 mL) was added DIEA (440 uL, 2.53 mmol) and PyBOP (316 mg, 607 umol). The mixture was stirred at room temperature for 30 minutes, 4,4-dimethyl-1,4-azasilinane hydrochloride (252 mg, 1.52 mmol) was added. The final mixture was stirred at 40 ℃ for 16 hours. After cooling to room temperature, the reaction mixture was quenched with water (30 mL), extracted with EtOAc (50 mL x 2). The combined organic layers were washed with water (30 mL x 3) and brine (30 mL), dried over anhydrous Na2SO4, concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give tert-butyl 2-((1-(2-(4,4-dimethyl- 1,4-azasilinan-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (200 mg, 78%) as a white solid. MS: m/z 507.3 (M+H+). Step 2 - Synthesis of 2-((1-(2-(4,4-dimethyl-1,4-azasilinan-1-yl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid To a solution of tert-butyl 2-((1-(2-(4,4-dimethyl-1,4-azasilinan-1-yl)-7-methyl-4-oxo- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (150 mg, 296 umol) in DCM (6 mL) was added TFA (2 mL). The mixture was stirred at 50 °C for 16 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 3% - 33% / 0.225% formic acid in water) to give 2- ((1-(2-(4,4-dimethyl-1,4-azasilinan-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (90 mg, 67%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 8.52 (s, 1H), 8.40 (d, J = 5.6 Hz, 1H), 7.80 (dd, J = 8.0, 1.6 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.25 - 7.17 (m, 1H), 6.56 - 6.52 (m, 1H), 6.35 (d, J = 8.8 Hz, 1H), 5.59 (s, 1H), 5.26 - 5.19 (m, 1H), 3.89 - 3.83 (m, 4H), 2.23 (s, 3H), 1.58 (d, J = 6.8 Hz, 3H), 0.86 - 0.74 (m, 4H), 0.10 (s, 6H). MS: m/z 451.2 (M+H+). Step 3 - Synthesis of (R)-2-((1-(2-(4,4-dimethyl-1,4-azasilinan-1-yl)-7-methyl-4-oxo- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 446) and (S)-2-((1- (2-(4,4-dimethyl-1,4-azasilinan-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid 2-((1-(2-(4,4-dimethyl-1,4-azasilinan-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin- 9-yl)ethyl)amino)benzoic acid (85 mg, 189 umol) was separated by using chiral SFC (REGIS (S, S) WHELK-O1 (250mm*25mm,10um); Supercritical CO2 / EtOH+0.1% NH3•H2O = 70/30; 80 mL/min) to afford (R)-2-((1-(2-(4,4-dimethyl-1,4-azasilinan-1-yl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (16 mg, first peak) and (S)-2-((1-(2-(4,4- dimethyl-1,4-azasilinan-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (25 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. Compound 446: 1H NMR (400 MHz, DMSO-d6) δ 8.53 - 8.43 (m, 2H), 7.81 (dd, J = 8.0, 4.0 Hz, 1H), 7.56 (d, J = 1.6 Hz, 1H), 7.20 - 7.16 (m, 1H), 6.55 - 6.51 (m, 1H), 6.33 (d, J = 8.4 Hz, 1H), 5.59 (s, 1H), 5.27 - 5.17 (m, 1H), 3.90 - 3.84 (m, 4H), 2.22 (s, 3H), 1.57 (d, J = 6.8 Hz, 3H), 0.84 - 0.73 (m, 4H), 0.10 (s, 6H). MS: m/z 451.2 (M+H+). Example 17: Preparation of 2-(((R)-1-(7-methyl-2-((S)-1-methylisoindolin-2-yl)-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 652)
Figure imgf000292_0001
Step 1 - Synthesis of tert-butyl 2-((1-(7-methyl-2-(1-methylisoindolin-2-yl)-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate To a solution of tert-butyl 2-((1-(2-hydroxy-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin- 9-yl)ethyl)amino)benzoate (200 mg, 506 umol) in DMF (2 mL) was added PyBOP (316 mg, 607 umol) and DIEA (440 uL, 2.53 mmol). The reaction mixture was stirred at room temperature for 10 min, then 1-methylisoindoline hydrochloride (129 mg, 759 umol) was added. The reaction mixture was stirred at 60 °C for 16 hours. After cooling to room temperature, the reaction was quenched with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with aq. HCl (1 M, 30 mL) and brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 70% EtOAc in petroleum ether) to give tert-butyl 2-((1-(7- methyl-2-(1-methylisoindolin-2-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoate (200 mg, 77%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 0.8 Hz, 1H), 8.29 (d, J = 5.2 Hz, 1H), 7.80 - 7.73 (m, 1H), 7.67 - 7.62 (m, 1H), 7.42 - 7.37 (m, 2H), 7.34 - 7.31 (m, 2H), 7.27 - 7.20 (m, 1H), 6.60 - 6.51 (m, 1H), 6.50 - 6.29 (m, 1H), 5.71 - 5.40 (m, 2H), 5.39 - 5.29 (m, 1H), 4.95 - 4.57 (m, 2H), 2.26 (s, 3H), 1.67 (d, J = 6.8 Hz, 3H), 1.62 (s, 3H), 1.57 - 1.52 (m, 9H). MS: m/z 511.2 (M+H+). Step 2 - Synthesis of tert-butyl 2-(((R)-1-(7-methyl-2-((S)-1-methylisoindolin-2-yl)-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate, tert-butyl 2-(((S)-1-(7-methyl-2- ((S)-1-methylisoindolin-2-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate, tert-butyl 2-(((R)-1-(7-methyl-2-((R)-1-methylisoindolin-2-yl)-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate, tert-butyl 2-(((S)-1-(7-methyl-2-((R)-1- methylisoindolin-2-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate tert-butyl 2-((1-(7-methyl-2-(1-methylisoindolin-2-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin- 9-yl)ethyl)amino)benzoate (200 mg, 392 umol) was separated by using chiral SFC (DAICEL CHIRALCEL OD-H (250 mm*30 mm,5 um); Supercritical CO2 / EtOH + 0.1% NH3•H2O = 75/25; 80 mL/min) to afford tert-butyl 2-(((R)-1-(7-methyl-2-((S)-1-methylisoindolin-2-yl)-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (35 mg, first peak), tert-butyl 2-(((S)- 1-(7-methyl-2-((S)-1-methylisoindolin-2-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoate (33 mg, second peak), tert-butyl 2-(((R)-1-(7-methyl-2-((R)-1- methylisoindolin-2-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (32 mg, third peak) and tert-butyl 2-(((S)-1-(7-methyl-2-((R)-1-methylisoindolin-2-yl)-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (33 mg, fourth peak) both as yellow solid. Absolute configuration was arbitrarily assigned to each enantiomer. MS: m/z 511.2 (M+H+). Step 3 - Synthesis of 2-(((R)-1-(7-methyl-2-((S)-1-methylisoindolin-2-yl)-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid To a mixture of tert-butyl 2-(((R)-1-(7-methyl-2-((S)-1-methylisoindolin-2-yl)-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (35 mg, 69 umol) in DCM (3 mL) was added TFA (1 mL). The reaction was stirred at room temperature for 16 hours. This mixture was concentrated in vacuo and then diluted with MeOH (2 mL). The solution was adjusted pH to 10 with aq. LiOH (2 M), then adjusted pH to 6 with formic acid. The solution was purified by reverse phase chromatography (acetonitrile 65 - 95% / 0.225% formic acid in water) to give 2- (((R)-1-(7-methyl-2-((S)-1-methylisoindolin-2-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (Compound 680) (13 mg, 40%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.63 (s, 1H), 8.59 (s, 1H), 8.49 (s, 1H), 7.81 (d, J = 6.8 Hz, 1H), 7.63 (s, 1H), 7.43 - 7.37 (m, 2H), 7.36 - 7.30 (m, 2H), 7.23 - 7.19 (m, 1H), 6.56 - 6.52 (m, 1H), 6.40 (s, 1H), 5.74 - 5.30 (m, 3H), 5.02 - 4.56 (m, 2H), 2.26 (s, 3H), 1.65 - 1.51 (m, 6H). MS: m/z 455.2 (M+H+). Example 18: Preparation of (R)-2-((1-(7-methyl-4-oxo-2-(2-oxo-2,3- dihydrobenzo[d]thiazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 593)
Figure imgf000294_0001
Step 1 - Synthesis of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol- 2(3H)-one To a solution of 5-chloro-3H-1,3-benzothiazol-2-one (1 g, 5.39 mmol) and 4,4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (4.1 g, 16.16 mmol) in dioxane (10 mL) was added Xphos-Pd-G2 (424 mg, 539 umol) and KOAc (1.59 g, 16.16 mmol). The reaction mixture was stirred at 110 °C for 2 h under N2 atmosphere. After cooling to room temperature, the reaction was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 20% EtOAc in petroleum ether) to give 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2(3H)- one (1.4 g, 93%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.39 (dd, J = 7.6, 1.2 Hz, 1H), 7.36 (d, J = 1.2 Hz, 1H), 1.29 (s, 12H). MS: m/z 277.8 (M+H+). Step 2 - Synthesis of tert-butyl 2-((1-(7-methyl-4-oxo-2-(2-oxo-2,3- dihydrobenzo[d]thiazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate To a mixture of tert-butyl 2-((1-(7-methyl-4-oxo-2-(((trifluoromethyl)sulfonyl)oxy)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (150 mg, 284 umol) and 5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2(3H)-one (158 mg, 569 umol) in dioxane (2 mL) and water (0.2 mL) was added K2CO3 (118 mg, 853 umol) and Pd(PPh3)4 (33 mg, 29 umol). The mixture was stirred at 100 °C for 2 hours under N2 atmosphere. After cooling to room temperature, the reaction was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 40% EtOAc in petroleum ether) to give tert- butyl 2-((1-(7-methyl-4-oxo-2-(2-oxo-2,3-dihydrobenzo[d]thiazol-5-yl)-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (36 mg, 24%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.06 (s, 1H), 8.76 (s, 1H), 8.34 (d, J = 6.4 Hz, 1H), 8.06 (d, J = 1.2 Hz, 1H), 8.01 (dd, J = 8.4, 1.6 Hz, 1H), 7.81 (s, 1H), 7.79 - 7.71 (m, 2H), 7.22 - 7.18 (m, 1H), 7.01 (s, 1H), 6.59 - 6.52 (m, 2H), 6.45 (d, J = 8.4 Hz, 1H), 5.56 - 5.50 (m, 1H), 2.36 (s, 3H), 1.71 (d, J = 6.4 Hz, 3H), 1.53 (s, 9H). MS: m/z 529.2 (M+H+). Step 3 - Synthesis of tert-butyl (R)-2-((1-(7-methyl-4-oxo-2-(2-oxo-2,3- dihydrobenzo[d]thiazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate & tert- butyl (S)-2-((1-(7-methyl-4-oxo-2-(2-oxo-2,3-dihydrobenzo[d]thiazol-5-yl)-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate tert-butyl 2-((1-(7-methyl-4-oxo-2-(2-oxo-2,3-dihydrobenzo[d]thiazol-5-yl)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (94 mg, 178 umol) was separated by using chiral SFC (DAICEL CHIRALCEL OD-H (250 mm*30 mm,5 um); Supercritical CO2 / EtOH + 0.1% NH3•H2O = 50/50; 60 ml/min) to afford tert-butyl (R)-2-((1-(7-methyl-4-oxo-2-(2-oxo-2,3- dihydrobenzo[d]thiazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (12 mg, first peak) and tert-butyl (S)-2-((1-(7-methyl-4-oxo-2-(2-oxo-2,3-dihydrobenzo[d]thiazol-5-yl)- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (12 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. MS: m/z 529.2 (M+H+). Step 4 - Synthesis of (R)-2-((1-(7-methyl-4-oxo-2-(2-oxo-2,3-dihydrobenzo[d]thiazol- 5-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid To a mixture of tert-butyl (R)-2-((1-(7-methyl-4-oxo-2-(2-oxo-2,3- dihydrobenzo[d]thiazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (12 mg, 23 umol) in DCM (1 mL) was added TFA (0.5 mL). The reaction was stirred at room temperature for 16 hours. This mixture was concentrated in vacuo and then dissolved in MeOH (2 mL). The mixture was adjusted pH to 10 with aq. LiOH (2 M), then adjusted pH to 6 with formic acid. The solution was purified by reverse phase chromatography (acetonitrile 45 - 75% / 0.225% formic acid in water) to give (R)-2-((1-(7-methyl-4-oxo-2-(2-oxo-2,3-dihydrobenzo[d]thiazol-5-yl)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 613) (4 mg, 35%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.70 - 8.57 (m, 1H), 8.08 (s, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 6.8 Hz, 1H), 7.78 (d, J = 1.2 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.19 - 7.15 (m, 1H), 7.01 (s, 1H), 6.56 - 6.52 (m, 1H), 6.39 (d, J = 8.8 Hz, 1H), 5.60 - 5.49 (m, 1H), 2.35 (s, 3H), 1.67 (d, J = 6.4 Hz, 3H). MS: m/z 473.0 (M+H+). Example 19: Preparation of (R)-2-((1-(2-(4-fluorophenyl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 424)
Figure imgf000296_0001
Step 1 - Synthesis of tert-butyl 2-((1-(2-(4-fluorophenyl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate To a mixture of tert-butyl 2-((1-(7-methyl-4-oxo-2-(((trifluoromethyl)sulfonyl)oxy)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (100 mg, 189 umol), K2CO3 (79 mg, 0.56 mmol) and (4-fluorophenyl)boronic acid (53 mg, 379 umol) in dioxane (3 mL) and water (0.3 mL), Pd(PPh3)4 (22 mg, 19 umol) was added. The reaction mixture was heated to 100 °C and stirred for 2 hours under N2 atmosphere. After cooling to room temperature, the reaction was diluted with water (20 mL) and EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give tert-butyl 2-((1-(2-(4-fluorophenyl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (72 mg, 80%) as a white solid. 1H NMR (400 MHz, DMSO-d6) 8.76 (s, 1H), 8.41 - 8.27 (m, 3H), 7.85 - 7.73 (m, 2H), 7.41 - 7.33 (m, 2H), 7.25 - 7.16 (m, 1H), 7.05 (s, 1H), 6.58 - 6.51 (m, 1H), 6.46 (d, J = 8.4 Hz, 1H), 5.55 - 5.48 (m, 1H), 2.35 (s, 3H), 1.69 (d, J = 6.8 Hz, 3H), 1.54 (s, 9H). MS: m/z 474.2 (M+H+). Step 2 - Synthesis of 2-((1-(2-(4-fluorophenyl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid To a mixture of tert-butyl 2-((1-(2-(4-fluorophenyl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (70 mg, 148 umol) in DCM (1.5 mL) was added TFA (0.5 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 3% MeOH in DCM) to give 2-((1-(2-(4-fluorophenyl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (57 mg, 35%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 8.76 (s, 1H), 8.50 (d, J = 6.0 Hz, 1H), 8.39 - 8.32 (m, 2H), 7.85 - 7.75 (m, 2H), 7.41 - 7.33 (m, 2H), 7.24 - 7.15 (m, 1H), 7.06 (s, 1H), 6.58 - 6.51 (m, 1H), 6.41 (d, J = 8.8 Hz, 1H), 5.60 - 5.51 (m, 1H), 2.34 (s, 3H), 1.67 (d, J = 6.8 Hz, 3H). MS: m/z 418.0 (M+H+). Step 3 - Synthesis of (R)-2-((1-(2-(4-fluorophenyl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 438) and (S)-2-((1-(2-(4- fluorophenyl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid 2-((1-(2-(4-fluorophenyl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (30 mg, 72 umol) was separated by using chiral SFC (DAICEL CHIRALCEL IC (250mm*30mm,10um); Supercritical CO2 / EtOH+0.1% NH3•H2O = 50/50; 70 mL/min) to afford (R)-2-((1-(2-(4-fluorophenyl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin- 9-yl)ethyl)amino)benzoic acid (10 mg, first peak) and (S)-2-((1-(2-(4-fluorophenyl)-7-methyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (4 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. Compound 438: 1H NMR (400 MHz, DMSO-d6) δ 12.80 (s, 1H), 8.75 (s, 1H), 8.57 - 8.47 (m, 1H), 8.38 - 8.32 (m, 2H), 7.84 - 7.79 (m, 1H), 7.77 (s, 1H), 7.41 - 7.33 (m, 2H), 7.22 - 7.16 (m, 1H), 7.06 (s, 1H), 6.58 - 6.50 (m, 1H), 6.41 (d, J = 8.4 Hz, 1H), 5.59 - 5.50 (m, 1H), 2.34 (s, 3H), 1.67 (d, J = 6.8 Hz, 3H). MS: m/z 418.0 (M+H+). Example 20: Preparation of (R)-2-((1-(2-(1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5- yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 696)
Figure imgf000298_0001
Step 1 - Synthesis of 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazolo[3,4-b]pyridine A mixture of 5-bromo-1,3-dimethyl-pyrazolo[3,4-b]pyridine (710 mg, 3.14 mmol) (prepared according to the procedure in WO2016123629), Pd(dppf)Cl2 (230 mg, 314 umol), KOAc (925 mg, 9.42 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1,3,2-dioxaborolane (2.39 g, 9.42 mmol) in dioxane (8 mL) was stirred at 100 ºC for 2 hours under N2 atmosphere. After cooling to room temperature, the reaction was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridine (700 mg, 82%) as a brown solid. MS: m/z 274.1 (M+H+). Step 2 - Synthesis of tert-butyl 2-((1-(2-(1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5- yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate To a solution of tert-butyl 2-((1-(7-methyl-4-oxo-2-(((trifluoromethyl)sulfonyl)oxy)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (193 mg, 366 umol), 1,3-dimethyl-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridine (200 mg, 732 umol), K2CO3 (152 mg, 1.10 mmol) in dioxane (2 mL) and water (0.2 mL) was added Pd(PPh3)4 (42 mg, 37 umol). The reaction mixture was stirred at 100 °C for 2 hours under N2 atmosphere. After cooling to room temperature, the mixture was diluted with EtOAc (60 mL), washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give tert-butyl 2-((1-(2-(1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (90 mg, 47%) as a brown solid. MS: m/z 525.1 (M+H+). Step 3 - Synthesis of tert-butyl (R)-2-((1-(2-(1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin- 5-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate & tert-butyl (S)-2-((1-(2-(1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate tert-butyl 2-((1-(2-(1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (70 mg, 133 umol) was separated by using chiral SFC (DAICEL CHIRALCEL AD (250mm*30mm,5um); Supercritical CO2 / i-PrOH + 0.1% NH3•H2O = 70/30; 60 ml/min) to afford tert-butyl (R)-2-((1-(2-(1,3-dimethyl-1H- pyrazolo[3,4-b]pyridin-5-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoate (20 mg, first peak) and tert-butyl (S)-2-((1-(2-(1,3-dimethyl-1H- pyrazolo[3,4-b]pyridin-5-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoate (25 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. MS: m/z 525.1 (M+H+). Step 4 - Synthesis of (R)-2-((1-(2-(1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-7- methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid To a mixture of tert-butyl (R)-2-((1-(2-(1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-7- methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (20 mg, 38 umol) in DCM (1 mL) was added TFA (0.5 mL). The reaction was stirred at room temperature for 16 h. The mixture was concentrated in vacuo and then diluted with MeOH (2 mL). The solution was adjusted pH to 10 with aq. LiOH (2 M), then adjusted pH to 6 with formic acid. The solution was purified by reverse phase chromatography (acetonitrile 30 - 70% / 0.225% formic acid in water) to give (R)-2-((1-(2-(1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 726) (7 mg, 23%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.49 (d, J = 2.0 Hz, 1H), 9.10 (d, J = 2.0 Hz, 1H), 8.78 (s, 1H), 8.71 - 8.59 (m, 1H), 7.84 - 7.79 (m, 2H), 7.24 (s, 1H), 7.21 - 7.17 (m, 1H), 6.56 - 6.52 (m, 1H), 6.47 (d, J = 8.4 Hz, 1H), 5.62 - 5.53 (m, 1H), 4.03 (s, 3H), 2.59 (s, 3H), 2.36 (s, 3H), 1.71 (d, J = 6.4 Hz, 3H). MS: m/z 469.1 (M+H+). Example 21: Preparation of 2-((1-(2-(1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)- 3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 1411)
Figure imgf000300_0001
Step 1 - Synthesis of tert-butyl 2-((1-(2-(1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5- yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate To a solution of tert-butyl 2-((1-(3,7-dimethyl-4-oxo-2-(((trifluoromethyl)sulfonyl)oxy)- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (100 mg, 185 umol), 1,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridine (101 mg, 369 umol) and K2CO3 (77 mg, 554 umol) in dioxane (2 mL) and water (0.2 mL) was added Pd(PPh3)4 (21 mg, 18 umol). The reaction mixture was stirred at 100 °C for 2 hours under N2 atmosphere. After cooling to room temperature, the mixture was diluted with EtOAc (50 mL), washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (solvent gradient: 0 - 25% EtOAc in petroleum ether) to give the title compound (34 mg, 34%) as a brown solid. MS: m/z 539.1 (M+H+). Step 2 - Synthesis of 2-((1-(2-(1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-3,7- dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid To a mixture of tert-butyl 2-((1-(2-(1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-3,7- dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (34 mg, 63 umol) in DCM (3 mL) was added TFA (1 mL). The reaction was stirred at room temperature for 16 h. This mixture was concentrated in vacuo and then diluted with MeOH (2 mL). The solution was adjusted pH to 10 with aq. LiOH (2 M), then adjusted pH to 6 with formic acid. The solution was purified by reverse phase chromatography (acetonitrile 50 - 80% / 0.225% formic acid in water) to give 2-((1-(2-(1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 752) (11 mg, 36%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.94 (d, J = 2.0 Hz, 1H), 8.72 (s, 1H), 8.56 (d, J = 2.0 Hz, 1H), 8.51 (s, 1H), 7.81 (dd, J = 8.0, 1.6 Hz, 1H), 7.68 (d, J = 1.6 Hz, 1H), 7.20 - 7.16 (m, 1H), 6.55 - 7.51 (m, 1H), 6.39 (d, J = 8.4 Hz, 1H), 5.48 - 5.34 (m, 1H), 4.03 (s, 3H), 2.56 (s, 3H), 2.34 (s, 3H), 2.30 (s, 3H), 1.62 (d, J = 6.4 Hz, 3H). MS: m/z 483.1 (M+H+). Example 22: Preparation of 2-((1-(3,7-dimethyl-4-oxo-2-(1,2,3-trimethyl-1H- pyrrolo[2,3-b]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 1410)
Figure imgf000301_0001
Step 1 - Synthesis of 5-bromo-1,2,3-trimethyl-1H-pyrrolo[2,3-b]pyridine To a solution of 5-bromo-2,3-dimethyl-1H-pyrrolo[2,3-b]pyridine (1.11 g, 4.93 mmol) (prepared according to the procedure in US201182138) in DMF (10 mL) was added NaH (237 mg, 5.92 mmol, 60% purity) and MeI (338 uL, 5.42 mmol) under N2 atmosphere at 0 ºC. The mixture was stirred at 0 ºC for 2 hours. The reaction was quenched with sat. aq. NH4Cl (20 mL), diluted with water (20 mL), extracted with EtOAc (60 mL x 2). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 20% EtOAc in petroleum ether) to give 5-bromo-1,2,3-trimethyl-1H-pyrrolo[2,3-b]pyridine (1.1 g, 93%) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 2.0 Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), 3.75 (s, 3H), 2.38 (s, 3H), 2.20 (s, 3H). MS: m/z 241.0 (M+H+). Step 2 - Synthesis of 1,2,3-trimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrrolo[2,3-b]pyridine To a solution of 5-bromo-1,2,3-trimethyl-pyrrolo[2,3-b]pyridine (1 g, 4.18 mmol) in 1,4- dioxane (15 mL) was added Pd(dppf)Cl2 (306 mg, 418.22 μmol), KOAc (1.23 g, 12.55 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (3.19 g, 12.55 mmol). The reaction mixture was stirred at 80 °C for 16 hours under N2 atmosphere. After cooling to room temperature, EtOAc (100 mL) was added, and the mixture was washed with water (50 mL) and brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 25% EtOAc in petroleum ether) to give 1,2,3-trimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (1.14 g, 95%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 1.6 Hz, 1H), 8.04 (d, J = 1.6 Hz, 1H), 3.70 (s, 3H), 2.36 (s, 3H), 2.20 (s, 3H), 1.31 (s, 12H). MS: m/z 287.2 (M+H+). Step 3 - Synthesis of tert-butyl 2-((1-(3,7-dimethyl-4-oxo-2-(1,2,3-trimethyl-1H- pyrrolo[2,3-b]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate To a solution of tert-butyl 2-((1-(3,7-dimethyl-4-oxo-2-(((trifluoromethyl)sulfonyl)oxy)- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (190 mg, 349 μmol), K2CO3 (145 mg, 1.05 mmol) and 1,2,3-trimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3- b]pyridine (200 mg, 699 μmol) in dioxane (2 mL) and water (0.2 mL) was added Pd(PPh3)4 (40 mg, 35 μmol). The reaction was stirred at 100 ºC for 2 hours under N2 atmosphere. After cooling to room temperature, the reaction was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 5% MeOH in DCM) to give the title compound (190 mg, 98%) as a white solid. MS: m/z 552.2 (M+H+). Step 4 - Synthesis of 2-((1-(3,7-dimethyl-4-oxo-2-(1,2,3-trimethyl-1H-pyrrolo[2,3- b]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid To a mixture of tert-butyl 2-((1-(3,7-dimethyl-4-oxo-2-(1,2,3-trimethyl-1H-pyrrolo[2,3- b]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (13 mg, 24 umol) in DCM (1 mL) was added TFA (0.5 mL). The reaction was stirred at room temperature for 16 hours. This mixture was concentrated in vacuo and then diluted with MeOH (2 mL). The solution was adjusted pH to 10 with aq. LiOH (2 M), then adjusted pH to 6 with formic acid. The solution was purified by reverse phase chromatography (acetonitrile 50 - 80% / 0.225% formic acid in water) to give 2-((1-(3,7-dimethyl-4-oxo-2-(1,2,3-trimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 798) (3 mg, 25%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.56 (d, J = 2.0 Hz, 1H), 8.44 (d, J = 6.4 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 7.81 - 7.79 (m, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.23 - 7.17 (m, 1H), 6.56 - 6.52 (m, 1H), 6.39 (d, J = 8.4 Hz, 1H), 5.46 - 5.40 (m, 1H), 3.75 (s, 3H), 2.41 (s, 3H), 2.33 (s, 3H), 2.31 (s, 3H), 2.24 (s, 3H), 1.62 (d, J = 6.4 Hz, 3H). MS: m/z 496.2 (M+H+). Example 23: Preaparation of 2-(isoindolin-2-yl)-7-methyl-9-(1-((2-(pyridazin-4- yl)phenyl)amino)ethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (Compound 665)
Figure imgf000303_0001
Step 1 - Synthesis of 9-(1-((2-bromophenyl)amino)ethyl)-2-(isoindolin-2-yl)-7- methyl-4H-pyrido[1,2-a]pyrimidin-4-one A mixture of 9-(1-bromoethyl)-2-(isoindolin-2-yl)-7-methyl-4H-pyrido[1,2-a]pyrimidin- 4-one (50 mg, 0.13 mmol) and 2-bromoaniline (112 mg, 0.65 mmol) in dioxane (1 mL) was heated to 100 °C for 2 hours under N2 atmosphere. After cooling to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give 9-(1-((2- bromophenyl)amino)ethyl)-2-(isoindolin-2-yl)-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (370 mg, 59%) as colorless oil.1H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 7.53 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.40 - 7.31 (m, 4H), 7.03 - 6.98 (m, 1H), 6.59 - 6.52 (m, 1H), 6.34 (d, J = 8.0 Hz, 1H), 5.62 (s, 1H), 5.38 - 5.25 (m, 1H), 5.17 - 4.97 (m, 2H), 4.83 - 4.67 (m, 2H), 4.16 - 4.10 (m, 1H), 2.30 (s, 3H), 1.73 (br d, J = 6.8 Hz, 3H). MS: m/z 475.2(M+H+). Step 2 - Synthesis of 2-(isoindolin-2-yl)-7-methyl-9-(1-((2-(pyridazin-4- yl)phenyl)amino)ethyl)-4H-pyrido[1,2-a]pyrimidin-4-one To a solution of 9-(1-((2-bromophenyl)amino)ethyl)-2-(isoindolin-2-yl)-7-methyl-4H- pyrido[1,2-a]pyrimidin-4-one (200 mg, 0.42 mmol), Na2CO3 (134 mg, 1.26 mmol) and 4- (tributylstannyl)pyridazine (163 mg, 0.44 mmol) in 1,4-dioxane (2 mL) was added Pd(dppf)Cl2 (31 mg, 0.04 mmol). The reaction was stirred at 100 ºC for 16 hours under N2 atmosphere. After cooling to room temperature, the reaction was filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 55 - 85% / formic acid in water) to give 2-(isoindolin-2-yl)-7-methyl-9-(1-((2-(pyridazin-4-yl)phenyl)amino)ethyl)-4H- pyrido[1,2-a]pyrimidin-4-one (Compound 694) (16 mg, 8%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 7.23 (d, J = 5.2 Hz, 1H), 8.57 (s, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.81 (s, 1H), 7.41 - 7.40 (m, 1H), 7.34 - 7.32 (m, 1H), 7.14 - 7.10 (m, 1H), 6.81 - 6.79 (m, 1H), 6.55 - 6.50 (m, 1H), 5.84 (d, J = 7.6 Hz, 1H), 5.40 (s, 1H), 5.27 - 5.25 (m, 1H), 4.89 - 4.85 (m, 2H), 4.72 - 4.58 (m, 3H), 2.26 (s, 3H), 1.53 (d, J = 6.4 Hz, 3H). MS: m/z 475.0 (M+H+). Example 24: Preparation of 2-[[(1R)-1-[2-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-7- methyl-4-oxo-pyrido[1,2-a]pyrimidin-9-yl]ethyl]amino]benzenesulfonamide (Compound 730)
Figure imgf000304_0001
Step 1 - Synthesis of 2-[1-[2-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-7-methyl-4-oxo- pyrido[1,2-a]pyrimidin-9-yl]ethylamino]benzenesulfonamide To a solution of 2-[1-(2-hydroxy-7-methyl-4-oxo-pyrido[1,2-a]pyrimidin-9- yl)ethylamino]benzenesulfonamide (200 mg, 534 umol) in DMF (1 mL) was added PyBOP (334 mg, 641 umol) and DIEA (465 uL, 2.67 mmol). The mixture was stirred at room temperature for 20 min, (2S,6R)-2,6-dimethylmorpholine (92 mg, 801 umol) was added. The reaction was stirred at 40 °C for 16 hours. After cooling to room temperature, the reaction mixture was quenched with water (20 mL), extracted with EtOAc (50 mL x 2). The combined organic layers were washed with aq. HCl (1 M, 20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by Prep-TLC (10% MeOH in DCM) to give 2-[1-[2-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-7-methyl-4-oxo-pyrido[1,2- a]pyrimidin-9-yl]ethylamino]benzenesulfonamide (80 mg, 32%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 7.73 (d, J = 2.0 Hz, 1H), 7.64 (d, J = 6.4 Hz, 1H), 7.54 - 7.51 (m, 1H), 7.23 - 7.20 (m, 2H), 6.78 (d, J = 8.4 Hz, 1H), 6.43 - 6.36 (m, 2H), 5.83 (s, 1H), 5.76 (s, 1H), 5.29 - 5.22 (m, 1H), 3.63 - 3.58 (m, 2H), 2.60 - 2.55 (m, 4H), 2.23 (s, 3H), 1.57 (d, J = 6.4 Hz, 3H), 1.27 - 1.21 (m, 6H). MS: m/z 472.2 (M+H+). Step 2 - Synthesis of 2-[[(1R)-1-[2-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-7-methyl-4- oxo-pyrido[1,2-a]pyrimidin-9-yl]ethyl]amino]benzenesulfonamide & 2-[[(1S)-1-[2-[(2S,6R)- 2,6-dimethylmorpholin-4-yl]-7-methyl-4-oxo-pyrido[1,2-a]pyrimidin-9- yl]ethyl]amino]benzenesulfonamide 2-[1-[2-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-7-methyl-4-oxo-pyrido[1,2-a]pyrimidin-9- yl]ethylamino]benzenesulfonamide (60 mg, 127 umol) was separated by using chiral SFC (Phenomenex-Cellulose-2 (250mm*30mm,10um); Supercritical CO2 / EtOH+ 0.1% NH3•H2O = 50/50; 80 mL/min) to afford 2-[[(1R)-1-[2-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-7-methyl-4- oxo-pyrido[1,2-a]pyrimidin-9-yl]ethyl]amino]benzenesulfonamide (30 mg, first peak) and 2- [[(1S)-1-[2-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-7-methyl-4-oxo-pyrido[1,2-a]pyrimidin-9- yl]ethyl]amino]benzenesulfonamide (30 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. Compound 25: 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.73 (s, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.51 (s, 2H), 7.26 - 7.19 (m, 1H), 6.71 - 6.60 (m, 1H), 6.43 - 6.34 (m, 2H), 5.70 (s, 1H), 5.33 - 5.17 (m, 1H), 4.45 - 4.19 (m, 2H), 3.64 - 3.57 (m, 2H), 3.49 - 3.42 (m, 2H), 2.23 (s, 3H), 1.57 (d, J = 6.4 Hz, 3H), 1.17 - 1.12 (m, 6H). MS: m/z 472.2 (M+H+). Example 25: Preparation of (R)-2-((1-(2-(4,4-dimethylcyclohexyl)-7-methyl-4-oxo- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 623)
Figure imgf000305_0001
Step 1 - Synthesis of tert-butyl 2-((1-(2-(4,4-dimethylcyclohex-1-en-1-yl)-7-methyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate A mixture of tert-butyl 2-((1-(7-methyl-4-oxo-2-(((trifluoromethyl)sulfonyl)oxy)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (220 mg, 417 umol), 2-(4,4- dimethylcyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (148 mg, 625.58 umol), Pd(PPh3)4 (48 mg, 42 umol), K2CO3 (173 mg, 1.25 mmol) in dioxane (2 mL) and water (0.5 mL) was stirred at 100 °C for 2 hours under N2 atmosphere. The mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 20% EtOAc in petroleum ether) to give tert-butyl 2-((1-(2-(4,4-dimethylcyclohex-1- en-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (190 mg, 93%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.26 (d, J = 6.8 Hz, 1H), 7.79 - 7.75 (m, 1H), 7.74 - 7.71 (m, 1H), 7.24 - 7.20 (m, 1H), 7.15 (s, 1H), 6.57 - 6.53 (m, 1H), 6.48 - 6.39 (m, 2H), 5.45 - 5.24 (m, 1H), 2.32 (s, 3H), 2.09 (s, 2H), 1.65 (d, J = 6.8 Hz, 3H), 1.55 (s, 9H), 1.52 (t, J = 6.0 Hz, 2H), 1.31 - 1.22 (m, 4H), 0.97 - 0.94 (m, 6H). MS: m/z 488.1 (M+H+). Step 2 - Synthesis of tert-butyl 2-((1-(2-(4,4-dimethylcyclohexyl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate To a solution of tert-butyl 2-((1-(2-(4,4-dimethylcyclohex-1-en-1-yl)-7-methyl-4-oxo- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (150 mg, 300 umol) in MeOH (10 mL) was added wet Pd/C (0.2 g, 10% Pd, 50% wet with water). The reaction was stirred at room temperature for 2 h under H2 atmosphere (15 psi). The reaction was filtered through diatomaceous earth and the filtrate was concentrated in vacuo to afford tert-butyl 2-((1-(2-(4,4- dimethylcyclohexyl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (150 mg, crude) as yellow oil that required no further purification. MS: m/z 490.2 (M+H+). Step 3 - Synthesis of 2-((1-(2-(4,4-dimethylcyclohexyl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid To a solution of tert-butyl 2-((1-(2-(4,4-dimethylcyclohexyl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (100 mg, 204 umol) in DCM (3 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 80% - 100% / 0.225% formic acid in water) to give 2-((1-(2-(4,4- dimethylcyclohexyl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (45 mg, 50%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 8.69 (s, 1H), 8.45 (s, 1H), 7.81 (d, J = 6.8 Hz, 1H), 7.71 (s, 1H), 7.24 - 7.16 (m, 1H), 6.58 - 6.51 (m, 1H), 6.41 - 6.36 (m, 1H), 6.35 - 6.31 (m, 1H), 5.47 - 5.36 (m, 1H), 2.32 (s, 3H), 1.83 - 1.73 (m, 4H), 1.61 (d, J = 6.4 Hz, 3H), 1.53 - 1.45 (m, 2H), 1.39 - 1.30 (m, 2H), 0.98 - 0.93 (m, 6H). MS: m/z 434.1 (M+H+). Step 4 - Synthesis of (R)-2-((1-(2-(4,4-dimethylcyclohexyl)-7-methyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid & (S)-2-((1-(2-(4,4- dimethylcyclohexyl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid 2-((1-(2-(4,4-dimethylcyclohexyl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (40 mg, 85 umol) was separated by using chiral SFC (DAICEL CHIRALCEL OJ (250mm*30mm,10um); Supercritical CO2 / i-PrOH+0.1% NH3•H2O = 65/35; 80 mL/min) to afford (R)-2-((1-(2-(4,4-dimethylcyclohexyl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid (5 mg, first peak) and (S)-2-((1-(2-(4,4- dimethylcyclohexyl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (5 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. Compound 649: 1H NMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 8.69 (s, 1H), 8.44 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.75 - 7.70 (m, 1H), 7.24 - 7.16 (m, 1H), 6.58 - 6.51 (m, 1H), 6.41 - 6.36 (m, 1H), 6.33 (s, 1H), 5.47 - 5.36 (m, 1H), 2.32 (s, 3H), 1.83 - 1.73 (m, 4H), 1.61 (d, J = 6.4 Hz, 3H), 1.53 - 1.45 (m, 2H), 1.39 - 1.30 (m, 2H), 0.98 - 0.93 (m, 6H). MS: m/z 434.1 (M+H+). Example 26: Preparation of 2-(((R)-1-(2-((3R,5S)-3,5-dimethylpiperidin-1-yl)-7- methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 512)
Figure imgf000307_0001
Step 1 - Synthesis of tert-butyl 2-((1-(2-((3R,5S)-3,5-dimethylpiperidin-1-yl)-7- methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate To a solution of tert-butyl 2-((1-(2-hydroxy-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin- 9-yl)ethyl)amino)benzoate (100 mg, 0.25 mmol) in DMF (2 mL) was added PyBOP (158 mg, 0.30 mmol), DIEA (0.18 mL, 1.01 mmol). The mixture was stirred at room temperature for 30 minutes, (3R,5S)-3,5-dimethylpiperidine (114 mg, 1.01 mmol) was added. The reaction was stirred at 40 °C for 16 hours. After cooling to room temperature, the reaction mixture was quenched with water (20 mL), extracted with EtOAc (50 mL x 2). The combined organic layers were washed with aq. HCl (1 M, 20 mL) and brine (20 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 20% EtOAc in petroleum ether) to give tert-butyl 2-((1-(2-((3R,5S)-3,5- dimethylpiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (80 mg, 64%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.18 (d, J = 6.4 Hz, 1H), 7.78 - 7.76 (m, 1H), 7.59 (d, J = 1.6 Hz, 1H), 7.31 - 7.15 (m, 1H), 6.55 (t, J = 7.2 Hz, 1H), 6.39 (d, J = 8.8 Hz, 1H), 5.67 (s, 1H), 5.23 - 5.16 (m, 1H), 4.46 - 4.36 (m, 2H), 2.47 - 2.34 (m, 4H), 2.23 (s, 3H), 1.80 - 1.75 (m, 1H), 1.60 (d, J = 6.8 Hz, 3H), 1.57 (s, 9H), 0.89 (t, J = 6.4 Hz, 6H), 0.86 - 0.81 (m, 1H) MS: m/z 491.2 (M+H+). Step 2 - Synthesis of tert-butyl 2-(((R)-1-(2-((3R,5S)-3,5-dimethylpiperidin-1-yl)-7- methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate and tert-butyl 2-(((S)- 1-(2-((3R,5S)-3,5-dimethylpiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoate tert-butyl 2-((1-(2-((3R,5S)-3,5-dimethylpiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (80 mg, 137 umol) was separated by prep SFC (REGIS(S,S)WHELK-O1(250mm*25mm,10um), Supercritical CO2 / EtOH + 0.1% NH3•H2O = 55/45, 80 mL/min) to give tert-butyl 2-(((R)-1-(2-((3R,5S)-3,5-dimethylpiperidin-1-yl)-7-methyl- 4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (35 mg, first peak) and tert-butyl 2-(((S)-1-(2-((3R,5S)-3,5-dimethylpiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoate (35 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. MS: m/z 491.2 (M+H+). Step 3 – Synthesis of 2-(((R)-1-(2-((3R,5S)-3,5-dimethylpiperidin-1-yl)-7-methyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid To a mixture of tert-butyl 2-(((R)-1-(2-((3R,5S)-3,5-dimethylpiperidin-1-yl)-7-methyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (35 mg, 71 umol) in DCM (1.5 mL) was added TFA (0.5 mL). The reaction was stirred at room temperature for 16 hours. This mixture was concentrated in vacuo and then diluted with MeOH (2 mL). The solution was adjusted pH to 10 with aq. LiOH (2 M), then adjusted pH to 6 with formic acid. The solution was purified by reverse phase chromatography (acetonitrile 65 - 95% / 0.225% formic acid in water) to give 2-(((R)-1-(2-((3R,5S)-3,5-dimethylpiperidin-1-yl)-7-methyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 529) (10 mg, 33%) as a white solid. Compound 529: 1H NMR (400MHz, DMSO-d6) δ 12.73 (s, 1H), 8.51 (s, 1H), 8.40 (d, J = 5.6 Hz, 1H), 7.82 - 7.80 (m, 1H), 7.56 (s, 1H), 7.25-7.21 (m, 1H), 6.57 - 6.53 (m, 1H), 6.36 (d, J = 8.8 Hz, 1H), 5.67 (s, 1H), 5.23 - 5.19 (m, 1H), 4.55 - 4.25 (m, 2H), 2.44 - 2.36 (m, 2H), 2.22 (s, 3H), 1.82 - 1.78 (m, 1H), 1.61 - 1.55 (m, 5H), 0.90 - 0.88 (m, 6H), 0.87 - 0.79 (m, 1H). MS: m/z 435.1 (M+H+). Example 27: Preparation of (R)-2-((1-(3,7-dimethyl-4-oxo-2-(1,2,3-trimethyl-1H- pyrrolo[2,3-b]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 804)
Figure imgf000309_0001
Step 1 - Synthesis of tert-butyl (R)-2-((1-(3,7-dimethyl-4-oxo-2-(1,2,3-trimethyl-1H- pyrrolo[2,3-b]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate & tert- butyl (S)-2-((1-(3,7-dimethyl-4-oxo-2-(1,2,3-trimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate tert-butyl 2-[1-[3,7-dimethyl-4-oxo-2-(1,2,3-trimethylpyrrolo[2,3-b]pyridin-5- yl)pyrido[1,2-a]pyrimidin-9-yl]ethylamino]benzoate (190 mg, 344 μmol) was separated by using chiral SFC (DAICEL CHIRALPAK AD (250mm*30mm,10um); Supercritical CO2 / EtOH + 0.1% NH3•H2O = 80/20; 80 ml/min) to afford tert-butyl (R)-2-((1-(3,7-dimethyl-4-oxo-2-(1,2,3- trimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (75 mg, first peak) and tert-butyl (S)-2-((1-(3,7-dimethyl-4-oxo-2-(1,2,3-trimethyl-1H- pyrrolo[2,3-b]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (83 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. MS: m/z 552.3 (M+H+). Step 2 - Synthesis of (R)-2-((1-(3,7-dimethyl-4-oxo-2-(1,2,3-trimethyl-1H- pyrrolo[2,3-b]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid To a mixture of tert-butyl (R)-2-((1-(3,7-dimethyl-4-oxo-2-(1,2,3-trimethyl-1H- pyrrolo[2,3-b]pyridin-5-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (75 mg, 136 μmol) in DCM (3 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 60 - 90% / 0.225% formic acid in water) to give (R)- 2-((1-(3,7-dimethyl-4-oxo-2-(1,2,3-trimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 850) (50 mg, 74%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.75 (s, 1H), 8.71 (s, 1H), 8.57 (d, J = 1.6 Hz, 1H), 8.44 (d, J = 5.4 Hz, 1H), 8.17 (d, J = 1.6 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.65 (s, 1H), 7.22 - 7.18 (m, 1H), 6.54 (s, 1H), 6.39 (d, J = 8.4 Hz, 1H), 5.47 - 5.40 (m, 1H), 3.76 (s, 3H), 2.41 (s, 3H), 2.34 (s, 3H), 2.31 (s, 3H), 2.25 (s, 3H), 1.62 (d, J = 6.4 Hz, 3H). MS: m/z 496.1 (M+H+). Example 28: Preparation of (S)-2-(isoindolin-2-yl)-3,7-dimethyl-9-(1-((2-(pyridazin- 4-yl)phenyl)amino)ethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (Compound 848)
Figure imgf000310_0001
Step 1 - Synthesis of 9-bromo-2-(isoindolin-2-yl)-3,7-dimethyl-4H-pyrido[1,2- a]pyrimidin-4-one To a solution of 9-bromo-2-hydroxy-3,7-dimethyl-pyrido[1,2-a]pyrimidin-4-one (10 g, 37.2 mmol) in DMF (100 mL) was added PyBOP (25.1 g, 48.3 mmol) and DIEA (25.9 mL, 148.7 mmol). The mixture was stirred at room temperature for 30 minutes, isoindoline hydrochloride (6.9 g, 44.6 mmol) was added. The reaction was stirred at 90 °C for 16 hours. After cooling to room temperature, 1M aq. HCl (200 mL) solution was added and the suspension solution was filtered and the filter cake was dried in vacuo to give 9-bromo-2-(isoindolin-2-yl)- 3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (9.1 g, crude) as a yellow solid that required no further purification.1H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.14 (s, 1H), 7.42 - 7.37 (m, 2H), 7.33 - 7.29 (m, 2H), 5.16 (s, 4H), 2.40 - 2.37 (s, 3H), 2.33 - 2.31 (s, 3H). MS: m/z 371.8 (M+H+). Step 2 - Synthesis of 9-acetyl-2-(isoindolin-2-yl)-3,7-dimethyl-4H-pyrido[1,2- a]pyrimidin-4-one To a solution of 9-bromo-2-isoindolin-2-yl-3,7-dimethyl-pyrido[1,2-a]pyrimidin-4-one (5.2 g, 14.0 mmol) in dioxane (60 mL) was added Pd(dppf)Cl2 (514 mg, 702 umol) and tributyl(1-ethoxyvinyl)stannane (9.5 mL, 28.0 mmol). The mixture was stirred at 90 °C for 16 hours under N2 atmosphere. After cooling to room temperature, HCl (15 mL, 1 M) was added. The mixture was stirred at room temperature for 0.5 hours. The reaction mixture was added 100 mL 10% KF aqueous solution, stirred at room temperature for 2 hours. The suspension solution was filtered and the filter cake was washed with DCM (20 mL x 2) and MeOH (20 mL), dried in vacuo to give 9-acetyl-2-(isoindolin-2-yl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (3.5 g, crude) as a yellow solid that required no further purification.1H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 7.86 (s, 1H), 7.36 - 7.30 (m, 4H), 5.17 (s, 4H), 2.92 (s, 3H), 2.52 (s, 3H), 2.39 (s, 3H). MS: m/z 334.0 (M+H+). Step 3 - Synthesis of 9-(1-hydroxyethyl)-2-(isoindolin-2-yl)-3,7-dimethyl-4H- pyrido[1,2-a]pyrimidin-4-one To a solution of 9-acetyl-2-isoindolin-2-yl-3,7-dimethyl-pyrido[1,2-a]pyrimidin-4-one (3.5 g, 10.5 mmol) in MeOH (40 mL) was added NaBH4 (1.2 g, 31.5 mmol) at 0 °C. The mixture was stirred at room temperature for 16 hours under N2 atmosphere. The reaction was quenched with 1M HCl (10 mL) at 0°C. Then the suspension solution was filtered and the filter cake was washed with EtOAc (20 mL x 2) to give 9-(1-hydroxyethyl)-2-(isoindolin-2-yl)-3,7-dimethyl- 4H-pyrido[1,2-a]pyrimidin-4-one (3.5 g, crude) as a yellow solid that required no further purification.1H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 7.40 (s, 1H), 7.31 - 7.37 (m, 4H), 5.20 - 5.25 (m, 1H), 5.12 - 5.19 (m, 4H), 2.52 (s, 3H), 2.37 (s, 3H), 1.70 (d, J = 6.8 Hz, 3H). MS: m/z 336.1 (M+H+). Step 4 - Synthesis of 9-(1-bromoethyl)-2-(isoindolin-2-yl)-3,7-dimethyl-4H- pyrido[1,2-a]pyrimidin-4-one To a solution of 9-(1-hydroxyethyl)-2-(isoindolin-2-yl)-3,7-dimethyl-4H-pyrido[1,2- a]pyrimidin-4-one (1 g, 2.98 mmol) in DCM (20 mL) was added PBr3 (847 mg, 3.13 mmol) at 0 °C. The mixture was stirred at room temperature for 1 hour under N2 atmosphere. The mixture was quenched with sat. aq. NaHCO3 (20 mL), extracted with DCM (50 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 9-(1-bromoethyl)-2-(isoindolin-2-yl)-3,7-dimethyl-4H-pyrido[1,2- a]pyrimidin-4-one (1.2 g, crude) as a yellow solid that required no further purification.1H NMR (400 MHz, CDCl3) δ 8.83 (s, 1H), 7.95 (s, 1H), 7.43 - 7.37 (m, 4H), 5.89 - 6.08 (m, 1H), 5.33 - 5.45 (m, 4H), 2.90 (s, 3H), 2.52 (s, 3H), 2.17 (d, J = 6.4 Hz, 3H). Step 5 - Synthesis of 9-(1-((2-bromophenyl)amino)ethyl)-2-(isoindolin-2-yl)-3,7- dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one A mixture of 9-(1-bromoethyl)-2-(isoindolin-2-yl)-3,7-dimethyl-4H-pyrido[1,2- a]pyrimidin-4-one (100 mg, 251 umol) and 2-bromoaniline (86 mg, 502 umol) in dioxane (1 mL) was stirred at 90 °C for 2 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give 9-(1-((2-bromophenyl)amino)ethyl)-2- (isoindolin-2-yl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (80 mg, 80%) as a yellow solid. MS: m/z 491.2 (M+H+). Step 6 - Synthesis of 2-(isoindolin-2-yl)-3,7-dimethyl-9-(1-((2-(pyridazin-4- yl)phenyl)amino) ethyl)-4H-pyrido[1,2-a]pyrimidin-4-one To a solution of 9-(1-((2-bromophenyl)amino)ethyl)-2-(isoindolin-2-yl)-3,7-dimethyl- 4H-pyrido[1,2-a]pyrimidin-4-one (130 mg, 266 μmol) in dioxane (2 mL) was added Pd(dppf)Cl2 (19 mg, 27 μmol), Na2CO3 (84 mg, 797 μmol) and tributyl(pyridazin-4-yl)stannane (103 mg, 279 μmol). The mixture was stirred at 100 °C for 16 hours under N2 atmosphere. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 62 - 92% / 0.05% NH3•H2O+10 mM NH4HCO3 in water) to give 2-(isoindolin-2-yl)-3,7-dimethyl-9-(1-((2-(pyridazin-4-yl)phenyl)amino) ethyl)-4H- pyrido[1,2-a]pyrimidin-4-one (60 mg, 46%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 9.24 (d, J = 4.8 Hz, 1H), 8.55 (s, 1H), 7.88 (dd, J = 5.2, 2.4 Hz, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.38 - 7.43 (m, 2H), 7.29 - 7.34 (m, 2H), 7.09 - 7.15 (m, 2H), 6.73 - 6.68 (m, 1H), 6.45 (d, J = 8.8 Hz, 1H), 5.84 (d, J = 7.2 Hz, 1H), 5.29 - 5.25 (m, 1H), 5.19 - 5.12 (m, 2H), 5.01 - 5.09 (m, 2H), 2.42 (s, 3H), 2.27 (s, 3H), 1.51 (d, J = 6.8 Hz, 3H). MS: m/z 489.2 (M+H+). Step 7 - Synthesis of (R)-2-(isoindolin-2-yl)-3,7-dimethyl-9-(1-((2-(pyridazin-4- yl)phenyl)amino)ethyl)-4H-pyrido[1,2-a]pyrimidin-4-one & (S)-2-(isoindolin-2-yl)-3,7- dimethyl-9-(1-((2-(pyridazin-4-yl)phenyl)amino)ethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (Compound 909) 2-(isoindolin-2-yl)-3,7-dimethyl-9-(1-((2-(pyridazin-4-yl)phenyl)amino)ethyl)-4H- pyrido[1,2-a]pyrimidin-4-one (50 mg, 102 umol) was separated by using chiral SFC (DAICEL CHIRALCEL OD (250 mm * 30 mm, 10 um), Supercritical CO2 / EtOH + 0.1% NH4OH = 55/45;100 mL/min) to give (R)-2-(isoindolin-2-yl)-3,7-dimethyl-9-(1-((2-(pyridazin-4- yl)phenyl)amino)ethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (22 mg, first peak) and (S)-2- (isoindolin-2-yl)-3,7-dimethyl-9-(1-((2-(pyridazin-4-yl)phenyl)amino)ethyl)-4H-pyrido[1,2- a]pyrimidin-4-one (23 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. Compound 909: 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 9.24 (d, J = 5.6 Hz, 1H), 8.55 (s, 1H), 7.87 (dd, J = 5.2, 2.4 Hz, 1H), 7.72 (d, J = 1.2 Hz, 1H), 7.42 - 7.36 (m, 2H), 7.33 - 7.28 (m, 2H), 7.08 - 7.13 (m, 2H), 6.73 - 6.69 (m, 1H), 6.45 (d, J = 8.4 Hz, 1H), 5.83 (d, J = 7.2 Hz, 1H), 5.29 - 5.23 (m, 1H), 5.11 - 5.19 (m, 2H), 4.99 - 5.09 (m, 2H), 2.42 (s, 3H), 2.26 (s, 3H), 1.50 (d, J = 6.8 Hz, 3H). MS: m/z 489.2 (M+H+). Example 29: Preparation of (R)-2-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzenesulfonamide (Compound 856)
Figure imgf000313_0001
Step 1 - Synthesis of 2-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzenesulfonamide A mixture of 9-(1-bromoethyl)-2-(isoindolin-2-yl)-3,7-dimethyl-4H-pyrido[1,2- a]pyrimidin-4-one (500 mg, 1.26 mmol) and 2-aminobenzenesulfonamide (432 mg, 2.51 mmol) in dioxane (5 mL) was stirred at 90 °C for 2 hours. After cooling to room temperature, the reaction was concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 58 - 88% / 0.225% formic acid in water) to give 2-((1-(2-(isoindolin-2-yl)-3,7- dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzenesulfonamide (100 mg, 16%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.65 (dd, J = 8.0, 1.6 Hz, 1H), 7.54 (s, 2H), 7.41 (dd, J = 5.6, 3.2 Hz, 2H), 7.34 - 7.29 (m, 2H), 7.23 - 7.19 (m, 1H), 6.67 - 6.61 (m, 1H), 6.43 (d, J = 5.6 Hz, 1H), 6.39 (d, J = 8.4 Hz, 1H), 5.42 - 5.36 (m, 1H), 5.14 - 5.25 (m, 4H), 2.44 (s, 3H), 2.25 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H). MS: m/z 490.2 (M+H+). Step 2 - Synthesis of (R)-2-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzenesulfonamide (Compound 39) & (S)-2-((1-(2- (isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzenesulfonamide 2-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino) benzenesulfonamide (90 mg, 184 umol) was separated by chiral SFC (DAICEL CHIRALCEL Cellulose-4 (250 mm * 30 mm, 5 um), Supercritical CO2 / MeOH + 0.1% NH3•H2O = 40/60; 80 mL/min) to give (R)-2-((1-(2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzenesulfonamide (35 mg, first peak) and (S)-2-((1- (2-(isoindolin-2-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzenesulfonamide (29 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. Compound 919: 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 7.70 (d, J = 1.6 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.55 (s, 2H), 7.43 - 7.37 (m, 2H), 7.33 - 7.26 (m, 2H), 7.22 - 7.18 (m, 1H), 6.66 - 6.62 (m, 1H), 6.43 (d, J = 5.6 Hz, 1H), 6.38 (d, J = 8.4 Hz, 1H), 5.41 - 5.35 (m, 1H), 5.26 - 5.11 (m, 4H), 2.43 (s, 3H), 2.24 (s, 3H), 1.62 (d, J = 6.4 Hz, 3H). MS: m/z 490.1 (M+H+). Example 30: Preparation of 2-(isoindolin-2-yl)-3,7-dimethyl-9-(1-((2-(pyridazin-4- yl)thiophen-3-yl)amino)ethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (Compound 1409)
Figure imgf000314_0001
Step 1 - Synthesis of 9-(1-((2-bromothiophen-3-yl)amino)ethyl)-2-(isoindolin-2-yl)- 3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one To a solution of 9-(1-bromoethyl)-2-(isoindolin-2-yl)-3,7-dimethyl-4H-pyrido[1,2- a]pyrimidin-4-one (20 mg, 50 μmol) in DMF (2 mL) was added 2-bromothiophen-3-amine hydrobromide (15.6 mg, 60 μmol) (prepared according to the procedure in WO2016144848) and DIEA (26 uL, 150 μmol). The mixture was stirred at 90 °C for 16 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The resulting residue was purified by Prep- TLC (50% EtOAc in petroleum ether) to give 9-(1-((2-bromothiophen-3-yl)amino)ethyl)-2- (isoindolin-2-yl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (15 mg, 55%) as a yellow solid. MS: m/z 495.0 (M+H+). Step 2 - Synthesis of 2-(isoindolin-2-yl)-3,7-dimethyl-9-(1-((2-(pyridazin-4- yl)thiophen-3-yl)amino)ethyl)-4H-pyrido[1,2-a]pyrimidin-4-one To a solution of 9-(1-((2-bromothiophen-3-yl)amino)ethyl)-2-(isoindolin-2-yl)-3,7- dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (20 mg, 40 μmol) in dioxane (2 mL) was added Pd(PPh3)2Cl2 (3 mg, 4 μmol), Na2CO3 (13 mg, 120 μmol) and tributyl(pyridazin-4-yl)stannane (30 mg, 81 μmol). The mixture was stirred at 100 °C for 16 hours under N2 atmosphere. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 46 - 76% / 0.225% formic acid in water) to give 2- (isoindolin-2-yl)-3,7-dimethyl-9-(1-((2-(pyridazin-4-yl)thiophen-3-yl)amino)ethyl)-4H- pyrido[1,2-a]pyrimidin-4-one (Compound 963) (2.5 mg, 12%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.47 (d, J = 1.6 Hz, 1H), 9.08 (d, J = 6.0 Hz, 1H), 8.56 (s, 1H), 7.81 (s, 1H), 7.76 - 7.74 (m, 1H), 7.54 (d, J =5.2 Hz, 1H), 7.41 - 7.47 (m, 1H), 7.32 - 7.30 (m, 2H), 6.53 - 6.61 (m, 2H), 5.30 - 5.43 (m, 1H), 5.04 - 5.21 (m, 4H), 2.42 (s, 3H), 2.28 (s, 3H), 1.58 (d, J = 6.8 Hz, 3H). MS: m/z 495.2 (M+H+). Example 31: Preparation of (R)-2-((1-(2-(1,3-dimethyl-1H-indol-5-yl)-3,7-dimethyl- 4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 902)
Figure imgf000316_0001
Step 1 - Synthesis of 2-((1-(2-(1,3-dimethyl-1H-indol-5-yl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate To a solution of tert-butyl 2-((1-(3,7-dimethyl-4-oxo-2-(((trifluoromethyl)sulfonyl)oxy)- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (200 mg, 369 μmol ), K2CO3 (153 mg, 1.11 mmol) and 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole (100 mg, 369 μmol) (prepared according to the procedure in WO201910295) in dioxane (5 mL) and water (1 mL) was added Pd(PPh3)4 (43 mg, 37 μmol). The reaction was stirred at 100 ºC for 2 hours under N2 atmosphere. After cooling to room temperature, the reaction was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 15% EtOAc in petroleum) to give 2-((1-(2-(1,3-dimethyl-1H-indol-5-yl)-3,7- dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (150 mg, 76%) as a yellow solid. MS: m/z 537.2 (M+H+). Step 2 - Synthesis of 2-((1-(2-(1,3-dimethyl-1H-indol-5-yl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid To a mixture of 2-((1-(2-(1,3-dimethyl-1H-indol-5-yl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (150 mg, 280 μmol) in DCM (4 mL) was added TFA (2 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 63% - 93% / 0.225% formic acid in water) to give 2-((1-(2-(1,3-dimethyl-1H-indol- 5-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (90 mg, 67%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 8.69 (s, 1H), 8.43 ( d, J = 6.0 Hz, 1H), 7.88 (s, 1H), 7.83 - 7.78 (m, 1H), 7.66 - 7.62 (m, 1H), 7.63 (s, 1H), 7.60 - 7.54 (m, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.23 - 7.14 (m, 2H), 6.54 (t, J = 7.4 Hz, 1H), 6.39 (d, J = 8.4 Hz, 1H), 5.47 - 5.42 (m, 1H), 3.77 (s, 3H), 2.34 - 2.24 (m, 9H), 2.07 (s, 1H), 1.62 (d, J = 6.4 Hz, 3H). MS: m/z 481.2 (M+H+). Step 3 - Synthesis of (R)-2-((1-(2-(1,3-dimethyl-1H-indol-5-yl)-3,7-dimethyl-4-oxo- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 983) & (S)-2-((1-(2- (1,3-dimethyl-1H-indol-5-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid 2-((1-(2-(1,3-dimethyl-1H-indol-5-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (90 mg, 187 μmol) was separated by using chiral SFC (DAICEL CHIRALCEL OJ (250mm*30mm, 10um); Supercritical CO2 / EtOH+0.1% NH3•H2O = 65/35; 80 mL/min) to afford (R)-2-((1-(2-(1,3-dimethyl-1H-indol-5-yl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (25 mg, first peak) and (S)-2-((1-(2-(1,3- dimethyl-1H-indol-5-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (31 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. Compound 983: 1H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.47 ( s, 1H), 7.89 (s, 1H), 7.82 ( d, J = 7.2 Hz, 1H), 7.64 (s, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.23 - 7.17 (m, 2H), 6.54 (t, J = 7.8 Hz, 1H), 6.39 ( d, J = 8.4 Hz, 1H), 5.46 ( s, 1H), 3.78 (s, 3H), 2.35 - 2.28 (m, 9H), 1.62 ( d, J = 6.4 Hz, 3H). MS: m/z 481.1 (M+H+). Example 32: Preparation of (R)-2-((1-(2-(1-cyclopropyl-3-methyl-1H-indazol-5-yl)- 3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 892)
Figure imgf000317_0001
Step 1 - Synthesis of tert-butyl 2-((1-(2-(1-cyclopropyl-3-methyl-1H-indazol-5-yl)- 3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate To a solution of tert-butyl 2-((1-(3,7-dimethyl-4-oxo-2-(((trifluoromethyl)sulfonyl)oxy)- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (200 mg, 369 μmol ), K2CO3 (153 mg, 1.11 mmol) and 1-cyclopropyl-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- indazole (165 mg, 554 μmol) (prepared according to the procedure of 1-cyclopropyl-3-methyl-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole in WO201657834) in dioxane (2 mL) and water (0.2 mL) was added Pd(PPh3)4 (43 mg, 37 μmol). The reaction was stirred at 80 ºC for 16 hours under N2 atmosphere. After cooling to room temperature, the reaction was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 25% EtOAc in petroleum) to give tert-butyl 2-((1-(2-(1-cyclopropyl-3-methyl-1H- indazol-5-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (124 mg, 60%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.26 (d, J = 6.0 Hz, 1H), 8.04 (s, 1H), 7.85 - 7.80 (m, 1H), 7.70 (s, 1H), 7.24 - 7.18 (m, 1H), 6.54 (t, J = 7.6 Hz, 1H), 6.44 (d, J = 8.4 Hz, 1H), 5.43 - 5.37 (m, 1H), 3.72 - 3.65 (m, 1H), 2.35 (s, 3H), 2.30 (s, 3H), 1.64 (d, J = 6.8 Hz, 3H), 1.52 (s, 9H), 1.09 - 1.13 (m, 4H). MS: m/z 564.3 (M+H+). Step 2 - Synthesis of 2-((1-(2-(1-cyclopropyl-3-methyl-1H-indazol-5-yl)-3,7-dimethyl- 4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid To a mixture of tert-butyl 2-((1-(2-(1-cyclopropyl-3-methyl-1H-indazol-5-yl)-3,7- dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (124 mg, 220 μmol) in DCM (2 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 55% - 85% / 0.225% formic acid in water) to give 2-((1-(2-(1- cyclopropyl-3-methyl-1H-indazol-5-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (62 mg, 55%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.75 (s, 1 H), 8.71 (s, 1H), 8.42 (d, J = 6.0 Hz, 1H), 8.05 (s, 1H), 7.84 - 7.79 (m, 2H), 7.75 - 7.72 (m, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.24 - 7.15 (m, 1H), 6.56 - 6.52 (m, 1H), 6.38 (d, J = 8.4 Hz, 1H), 5.50 - 5.35 (m, 1H), 3.75 - 3.64 (m, 1H), 2.52 (s, 3H), 2.33 (s, 3H), 2.29 (s, 3H), 1.61 (d, J = 6.8 Hz, 3H), 1.17 - 1.06 (m, 4H). MS: m/z 508.3 (M+H+). Step 3 - Synthesis of (R)-2-((1-(2-(1-cyclopropyl-3-methyl-1H-indazol-5-yl)-3,7- dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 969) & (S)-2-((1-(2-(1-cyclopropyl-3-methyl-1H-indazol-5-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid 2-((1-(2-(1-cyclopropyl-3-methyl-1H-indazol-5-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid (62 mg, 122 μmol) was separated by using chiral SFC (DAICEL CHIRALPAK AD (250mm*30mm,10um); Supercritical CO2 / EtOH+0.1% NH3•H2O = 70/30; 80 mL/min) to afford (R)-2-((1-(2-(1-cyclopropyl-3-methyl-1H-indazol-5-yl)- 3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (22 mg, first peak) and (S)-2-((1-(2-(1-cyclopropyl-3-methyl-1H-indazol-5-yl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (20 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. Compound 969: 1H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.50 - 8.40 (m, 1H), 8.05 (s, 1H), 7.84 - 7.79 (m, 2H), 7.76 - 7.72 (m, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.23 - 7.15 (m, 1H), 6.56 - 6.52 (m, 1H), 6.38 (d, J = 8.4 Hz, 1H), 5.48 - 5.37 (m, 1H), 3.73 - 3.66 (m, 1H), 2.52 (s, 3H), 2.34 (s, 3H), 2.30 (s, 3H), 1.61 (d, J = 6.8 Hz, 3H), 1.13 - 1.08 (m, 4H). MS: m/z 508.2 (M+H+). Example 33: Preparation of (R)-2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 967)
Figure imgf000319_0001
Step 1 – Synthesis of tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate To a solution of tert-butyl 2-((1-(3,7-dimethyl-4-oxo-2-(((trifluoromethyl)sulfonyl)oxy)- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (180 mg, 332 μmol), K2CO3 (138 mg, 997 umol) and (3-cyanophenyl)boronic acid (73 mg, 499 μmol) in dioxane (3 mL) and water (0.3 mL) was added Pd(PPh3)4 (38 mg, 33 μmol). The reaction was stirred at 100 ºC for 2 hours under N2 atmosphere. After cooling to room temperature, the reaction was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (120 mg, 73%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.27 - 8.26 (m, 1H), 8.19 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.80 - 7.71 (m, 3H), 7.25 - 7.13 (m, 1H), 6.55 - 6.53 (m, 1H), 6.45 (d, J = 8.8 Hz, 1H), 5.38 - 5.34 (m, 1H), 2.35 (s, 3H), 2.22 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H), 1.53 (s, 9H). MS: m/z 495.3 (M+H+). Step 2 – Synthesis of 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid To a mixture of tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (60 mg, 121 μmol) in DCM (2 mL) was added TFA (0.5 mL, 6.9 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 58% - 88% / 0.225% formic acid in water) to give 2-((1-(2-(3-cyanophenyl)-3,7- dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (50 mg, 94%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 12.75 (s, 1H), 8.72 (s, 1H), 8.44 (s, 1H), 8.19 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.85 - 7.73 (m, 2H), 7.68 (d, J = 1.6 Hz, 1H), 7.21 - 7.19 (m 1H), 6.55 - 6.54 (m, 1H), 6.36 (d, J = 8.0 Hz, 1H), 5.41 - 5.39 (m, 1H), 2.34 (s, 3H), 2.23 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H). MS: m/z 439.2 (M+H+). Step 3 – Synthesis of (R)-2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 1071) & (S)-2-((1-(2-(3- cyanophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (50 mg, 114 μmol) was separated by using chiral SFC (DAICEL CHIRALCEL OJ (250mm*30mm,10um); Supercritical CO2 / EtOH+0.1% NH3•H2O = 75/25; 70 mL/min) to afford (R)-2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin- 9-yl)ethyl)amino)benzoic acid (Compound 1071) (4 mg, first peak) and (S)-2-((1-(2-(3- cyanophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (5 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. First peak: 1H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.45 (s, 1H), 8.19 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.83 - 7.73 (m, 2H), 7.68 (d, J = 1.6 Hz, 1H), 7.23 - 7.15 (m, 1H), 6.56 - 6.54 (m, 1H), 6.36 (d, J = 8.4 Hz, 1H), 5.43 - 5.36 (m, 1H), 2.34 (s, 3H), 2.23 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H). MS: m/z 439.2 (M+H+). Example 34: Preparation of (R)-2-((1-(2-(3-cyano-4-fluorophenyl)-3,7-dimethyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 947)
Figure imgf000321_0001
Step 1 – Synthesis of tert-butyl 2-((1-(2-(3-cyano-4-fluorophenyl)-3,7-dimethyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate Following the procedure described in Example 33, Step 1 and making non-critical variations as required to replace (3-cyanophenyl)boronic acid with (3-cyano-4-fluoro- phenyl)boronic acid, tert-butyl 2-((1-(2-(3-cyano-4-fluorophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (160 mg, 84%) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.36 - 8.27 (m, 2H), 8.21 - 8.11 (m, 1H), 7.79 - 7.65 (m, 3H), 7.20 - 7.18 (m, 1H), 6.53 - 6.51 (m, 1H), 6.46 (d, J = 8.4 Hz, 1H), 2.35 (s, 3H), 2.23 (s, 3H), 1.64 (d, J = 6.4 Hz, 3H), 1.52 (s, 9H). MS: m/z 513.3 (M+H+). Step 2 – Synthesis of 2-((1-(2-(3-cyano-4-fluorophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid Following the procedure described in Example 33, Step 2 and making non-critical variations as required to replace tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate with tert-butyl 2-((1-(2-(3-cyano-4- fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate, 2-((1- (2-(3-cyano-4-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (50 mg, 70%) was obtained as a white solid.1H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 8.72 (s, 1H), 8.52 - 8.35 (m, 1H), 8.30 - 8.29 (m, 1H), 8.20 - 8.12 (m, 1H), 7.80 - 7.79 (m, 1H), 7.73 - 7.68 (m, 2H), 7.23 - 7.15 (m, 1H), 6.55 - 6.54 (m, 1H), 6.36 (d, J = 8.4 Hz, 1H), 5.44 - 5.35 (m, 1H), 2.34 (s, 3H), 2.23 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H). MS: m/z 457.2 (M+H+). Step 3 – Synthesis of (R)-2-((1-(2-(3-cyano-4-fluorophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid & (S)-2-((1-(2-(3-cyano-4- fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid 2-((1-(2-(3-cyano-4-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (50 mg, 110 μmol) was separated by using chiral SFC (DAICEL CHIRALCEL OJ (250mm*30mm,10um); Supercritical CO2 / EtOH+0.1% NH3•H2O = 65/35; 70 mL/min) to afford (R)-2-((1-(2-(3-cyano-4-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 1041) (9 mg, first peak) and (S)-2-((1-(2- (3-cyano-4-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (9 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. First peak: 1H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.53 - 8.43 (m, 1H), 8.30 - 8.29 (m, 1H), 8.19 - 8.11 (m, 1H), 7.80 - 7.79 (m, 1H), 7.74 - 7.67 (m, 2H), 7.18 - 7.16 (m, 1H), 6.55 - 6.53 (m, 1H), 6.35 (d, J = 8.4 Hz, 1H), 5.43 - 5.34 (m, 1H), 2.34 (s, 3H), 2.23 (s, 3H), 1.59 (d, J = 6.4 Hz, 3H). MS: m/z 457.2 (M+H+). Example 35: Preparation of (R)-2-((1-(2-(4-chlorophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 963)
Figure imgf000322_0001
Step 1 – Synthesis of tert-butyl 2-((1-(2-(4-chlorophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate Following the procedure described in Example 33, Step 1 and making non-critical variations as required to replace (3-cyanophenyl)boronic acid with (4-chlorophenyl)boronic acid, tert-butyl 2-((1-(2-(4-chlorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoate (130 mg, 78%) was obtained as a white solid. MS: m/z 504.2 (M+H+). Step 2 – Synthesis of 2-((1-(2-(4-chlorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid Following the procedure described in Example 33, Step 2 and making non-critical variations as required to replace tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate with tert-butyl 2-((1-(2-(4-chlorophenyl)-3,7- dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate, 2-((1-(2-(4- chlorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (30 mg, 45%) was obtained as a white solid. MS: m/z 448.2 (M+H+). Step 3 – Synthesis of (R)-2-((1-(2-(4-chlorophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 45) & (S)-2-((1-(2-(4- chlorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid 2-((1-(2-(4-chlorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (20 mg, 45 umol) was separated by using chiral SFC (DAICEL CHIRALPAK AD(250mm*30mm,10um); Supercritical CO2 / EtOH + 0.1% NH3•H2O = 75/25; 70 mL/min) to afford (R)-2-((1-(2-(4-chlorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 1067) (2 mg, first peak) and (S)-2-((1-(2- (4-chlorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (3 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. First peak: 1H NMR (400 MHz, DMSO-d6) δ 12.76 (s, 1H), 8.70 (s, 1H), 8.47 (s, 1H), 7.85 - 7.72 (m, 3H), 7.68 - 7.67 (m, 1H), 7.63 - 7.60 (m, 2H), 7.24 - 7.11 (m, 1H), 6.58 - 6.50 (m, 1H), 6.35 (d, J = 8.8 Hz, 1H), 5.42 - 5.34 (m, 1H), 2.34 (s, 3H), 2.24 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H). MS: m/z 448.1 (M+H+). Example 36: Preparation of (R)-2-((1-(2-(4-chloro-2-fluorophenyl)-3,7-dimethyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 965)
Figure imgf000323_0001
Step 1 – Synthesis of tert-butyl 2-((1-(2-(4-chloro-2-fluorophenyl)-3,7-dimethyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate Following the procedure described in Example 33, Step 1 and making non-critical variations as required to replace (3-cyanophenyl)boronic acid with (4-chloro-2-fluoro- phenyl)boronic acid, tert-butyl 2-((1-(2-(4-chloro-2-fluorophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (135 mg, 78%) was obtained as a white solid. MS: m/z 522.2 (M+H+). Step 2 – Synthesis of 2-((1-(2-(4-chloro-2-fluorophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid Following the procedure described in Example 33, Step 2 and making non-critical variations as required to replace tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate with tert-butyl 2-((1-(2-(4-chloro-2- fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate, 2-((1- (2-(4-chloro-2-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (30 mg, 45%) was obtained as a white solid. MS: m/z 466.2 (M+H+). Step 3 – Synthesis of (R)-2-((1-(2-(4-chloro-2-fluorophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 1069) & (S)-2-((1-(2-(4- chloro-2-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid 2-((1-(2-(4-chloro-2-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (30 mg, 65 umol) was separated by using chiral SFC (DAICEL CHIRALPAK AD(250mm*30mm,10um); Supercritical CO2 / EtOH + 0.1% NH3•H2O = 70/30; 60 mL/min) to afford (R)-2-((1-(2-(4-chloro-2-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 1069) (12 mg, first peak) and (S)-2-((1- (2-(4-chloro-2-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (7 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. First peak: 1H NMR (400 MHz, DMSO-d6) δ 12.76 (s, 1H), 8.73 (s, 1H), 8.49 (s, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.71 - 7.61 (m, 3H), 7.51 - 7.47 (m, 1H), 7.21 - 7.12 (m, 1H), 6.58 - 6.49 (m, 1H), 6.32 (d, J = 8.8 Hz, 1H), 5.48 - 5.18 (m, 1H), 2.34 (s, 3H), 2.06 (s, 3H), 1.56 (d, J = 6.4 Hz, 3H). MS: m/z 466.1 (M+H+). Example 37: Preparation of (R)-2-((1-(2-(6-cyanopyridin-3-yl)-3,7-dimethyl-4-oxo- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 975)
Figure imgf000325_0001
Step 1 – Synthesis of tert-butyl 2-((1-(2-(6-cyanopyridin-3-yl)-3,7-dimethyl-4-oxo- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate Following the procedure described in Example 33, Step 1 and making non-critical variations as required to replace (3-cyanophenyl)boronic acid with (6-cyano-3-pyridyl)boronic acid, tert-butyl 2-((1-(2-(6-cyanopyridin-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoate (150 mg, 90%) was obtained as a white solid. MS: m/z 496.3 (M+H+). Step 2 – Synthesis of 2-((1-(2-(6-cyanopyridin-3-yl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid Following the procedure described in Example 33, Step 2 and making non-critical variations as required to replace tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate with tert-butyl 2-((1-(2-(6-cyanopyridin-3- yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate, 2-((1-(2-(6- cyanopyridin-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (30 mg, 17%) was obtained as a white solid. MS: m/z 440.2 (M+H+). Step 3 – Synthesis of (R)-2-((1-(2-(6-cyanopyridin-3-yl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 1081) & (S)-2-((1-(2-(6- cyanopyridin-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid 2-((1-(2-(6-cyanopyridin-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (20 mg, 46 umol) was separated by using chiral SFC (DAICEL CHIRALPAK AD (250mm*30mm,10um); Supercritical CO2 / EtOH + 0.1% NH3•H2O = 70/30; 60 mL/min) to afford (R)-2-((1-(2-(6-cyanopyridin-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 1081) (6 mg, first peak) and (S)-2-((1-(2- (6-cyanopyridin-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (5 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. First peak: 1H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 9.13 (d, J = 1.6 Hz, 1H), 8.74 (s, 1H), 8.51 - 8.45 (m, 1H), 8.44 - 8.40 (m, 1H), 8.23 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 7.2 Hz, 1H), 7.72 (s, 1H), 7.22 - 7.13 (m, 1H), 6.60 - 6.49 (m, 1H), 6.37 (d, J = 8.8 Hz, 1H), 5.45 - 5.28 (m, 1H), 2.35 (s, 3H), 2.24 (s, 3H), 1.60 (d, J = 6.4 Hz, 3H). MS: m/z 440.1 (M+H+). Example 38: Preparation of 2-((1-(3,7-dimethyl-4-oxo-2-(pyridin-4-yl)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 1408)
Figure imgf000326_0001
Step 1 - Synthesis of tert-butyl 2-((1-(3,7-dimethyl-4-oxo-2-(pyridin-4-yl)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate Following the procedure described in Example 33, Step 1 and making non-critical variations as required to replace (3-cyanophenyl)boronic acid with pyridin-4-ylboronic acid, tert- butyl 2-((1-(3,7-dimethyl-4-oxo-2-(pyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoate (130 mg, 83%) was obtained as a white solid. MS: m/z 471.3 (M+H+). Step 2 - Synthesis of 2-((1-(3,7-dimethyl-4-oxo-2-(pyridin-4-yl)-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid Following the procedure described in Example 33, Step 2 and making non-critical variations as required to replace tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate with tert-butyl 2-((1-(3,7-dimethyl-4-oxo-2- (pyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate, 2-((1-(3,7-dimethyl-4-oxo- 2-(pyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (30 mg, 68%) was obtained as a white solid.1H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 8.78 - 8.74 (m, 2H), 8.72 (s, 1H), 8.41 (d, J = 6.0 Hz, 1H), 7.83 - 7.78 (m, 1H), 7.76 - 7.72 (m, 2H), 7.70 (d, J = 1.6 Hz, 1H), 7.23 - 7.15 (m, 1H), 6.58 - 6.50 (m, 1H), 6.36 (d, J = 8.4 Hz, 1H), 5.44 - 5.31 (m, 1H), 2.34 (s, 3H), 2.23 (s, 3H), 1.60 (d, J = 6.4 Hz, 3H). MS: m/z 415.1 (M+H+). Example 39: Preparation of (R)-2-((1-(2-(3-fluorophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 969)
Figure imgf000327_0001
Step 1 – Synthesis of tert-butyl 2-((1-(2-(3-fluorophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate Following the procedure described in Example 33, Step 1 and making non-critical variations as required to replace (3-cyanophenyl)boronic acid with (3-fluorophenyl) boronic acid, tert-butyl 2-((1-(2-(3-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoate (120 mg, 67%) was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 7.89 (dd, J = 8.0, 1.6 Hz, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.51 - 7.40 (m, 3H), 7.20 - 7.10 (m, 2H), 6.60 - 6.51 (m, 1H), 6.29 (d, J = 8.4 Hz, 1H), 5.58 - 5.39 (m, 1H), 2.38 (s, 3H), 2.35 (s, 3H), 1.68 (d, J = 6.8 Hz, 3H), 1.64 (s, 9H). MS: m/z 488.1 (M+H+). Step 2 – Synthesis of 2-((1-(2-(3-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid Following the procedure described in Example 33, Step 2 and making non-critical variations as required to replace tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate with tert-butyl 2-((1-(2-(3-fluorophenyl)-3,7- dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate, 2-((1-(2-(3- fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (60 mg, 54%) was obtained as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 12.78 (s, 1H), 8.71 (s, 1H), 8.41 (d, J = 6.4 Hz, 1H), 7.86 - 7.75 (m, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.63 - 7.52 (m, 3H), 7.39 - 7.30 (m, 1H), 7.24 - 7.13 (m, 1H), 6.51 - 6.55 (m, J = 7.6 Hz, 1H), 6.35 (d, J = 8.8 Hz, 1H), 5.42 - 5.36 (m, 1H), 2.33 (s, 3H), 2.23 (s, 3H), 1.59 (d, J = 6.8 Hz, 3H). MS: m/z 432.2 (M+H+). Step 3 – Synthesis of (R)-2-((1-(2-(3-fluorophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 1073) & (S)-2-((1-(2-(3- fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid 2-((1-(2-(3-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (60 mg, 139 μmol) was separated by using chiral SFC (DAICEL CHIRALCEL OD (250 mm * 30 mm, 10 um), Supercritical CO2 / EtOH + 0.1% NH3•H2O = 55/45;100 mL/min) to afford (R)-2-((1-(2-(3-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 1073) (10 mg, first peak) and (S)-2-((1- (2-(3-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (13 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. First peak: 1H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.45 (s, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.67 (s, 1H), 7.60 - 7.53 (m, 3H), 7.37 - 7.31 (m, 1H), 7.21 - 7.16 (m, 1H), 6.55 - 6.51 (m, 1H), 6.35 (d, J = 8.4 Hz, 1H), 5.41 - 5.36 (m, 1H), 2.33 (s, 3H), 2.23 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H). MS: m/z 432.2 (M+H+). Example 40: Preparation of (R)-2-((1-(2-(3-(difluoromethyl)phenyl)-3,7-dimethyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 972)
Figure imgf000328_0001
Step 1 – Synthesis of tert-butyl 2-((1-(2-(3-(difluoromethyl)phenyl)-3,7-dimethyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate Following the procedure described in Example 33, Step 1 and making non-critical variations as required to replace (3-cyanophenyl)boronic acid with (3- (difluoromethyl)phenyl)boronic acid, tert-butyl 2-((1-(2-(3-(difluoromethyl)phenyl)-3,7- dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (160 mg, 83%) was obtained as a white solid.1H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 8.63 - 8.15 (m, 1H), 7.87 - 8.01 (m, 1H), 7.86 - 7.81 (m, 2H), 7.65 - 7.58 (m, 3H), 7.19 - 7.10 (m, 1H), 6.91 - 6.61 (m, 1H), 6.60 - 6.54 (m, 1H), 6.32 (d, J = 8.4 Hz, 1H), 5.52 - 5.48 (m, 1H), 2.37 (s, 3H), 2.36 (s, 3H), 1.69 (d, J = 6.8 Hz, 3H), 1.63 (s, 9H). MS: m/z 520.2 (M+H+). Step 2 – Synthesis of 2-((1-(2-(3-(difluoromethyl)phenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid Following the procedure described in Example 33, Step 2 and making non-critical variations as required to replace tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate with tert-butyl 2-((1-(2-(3- (difluoromethyl)phenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoate, 2-((1-(2-(3-(difluoromethyl)phenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (90 mg, 62%) was obtained as a white solid.1H NMR (400 MHz, DMSO-d6) δ 12.75 (s, 1H), 8.72 (s, 1H), 8.42 (d, J = 5.6 Hz, 1H), 7.96 - 7.88 (m, 2H), 7.81 (d, J = 6.8 Hz, 1H), 7.73 - 7.65 (m, 3H), 7.31 - 7.01 (m, 2H), 6.56 - 6.52 (m, 1H), 6.36 (d, J = 8.4 Hz, 1H), 5.42 - 5.36 (m, 1H), 2.34 (s, 3H), 2.23 (s, 3H), 1.60 (d, J = 6.4 Hz, 3H). MS: m/z 464.2 (M+H+). Step 3 – Synthesis of (R)-2-((1-(2-(3-(difluoromethyl)phenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 1077) & (S)-2-((1-(2-(3- (difluoromethyl)phenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid 2-((1-(2-(3-(difluoromethyl)phenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (90 mg, 194 μmol) was separated by using chiral SFC (DAICEL CHIRALCEL OD (250 mm * 30 mm, 10 um), Supercritical CO2 / EtOH + 0.1% NH3•H2O = 55/45;100 mL/min) to give (R)-2-((1-(2-(3-(difluoromethyl)phenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 1077) (22 mg, first peak) and (S)-2-((1-(2-(3-(difluoromethyl)phenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (29 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. First peak: 1H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.44 (s, 1H), 7.94 - 7.89 (m, 2H), 7.81 (d, J = 7.6 Hz, 1H), 7.72 - 7.66 (m, 3H), 7.30 - 7.01 (m, 2H), 6.55 - 6.50 (m, 1H), 6.36 (d, J = 8.4 Hz, 1H), 5.42 - 5.36 (m, 1H), 2.33 (s, 3H), 2.23 (s, 3H), 1.59 (d, J = 6.4 Hz, 3H). MS: m/z 464.3 (M+H+). Example 41: Preparation of (R)-2-((1-(2-(5-chloro-6-methylpyridin-3-yl)-3,7- dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 951)
Figure imgf000330_0001
Step 1 - Synthesis of tert-butyl 2-((1-(2-(5-chloro-6-methylpyridin-3-yl)-3,7-dimethyl- 4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate Following the procedure described in Example 33, Step 1 and making non-critical variations as required to replace (3-cyanophenyl)boronic acid with (5-chloro-6-methylpyridin-3- yl)boronic acid, tert-butyl 2-((1-(2-(5-chloro-6-methylpyridin-3-yl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (170 mg, 89%) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J = 2.0 Hz, 1H), 8.72 (s, 1H), 8.33 (d, J = 6.8 Hz, 1H), 8.22 (d, J = 2.0 Hz, 1H), 7.78 - 7.71 (m, 2H), 7.24 - 7.17 (m, 1H), 6.58 - 6.42 (m, 2H), 5.48 - 5.20 (m, 1H), 2.63 (s, 3H), 2.35 (s, 3H), 2.25 (s, 3H), 1.64 (d, J = 6.8 Hz, 3H), 1.51 (s, 9H). MS: m/z 519.1 (M+H+). Step 2 - Synthesis of 2-((1-(2-(5-chloro-6-methylpyridin-3-yl)-3,7-dimethyl-4-oxo- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid Following the procedure described in Example 33, Step 2 and making non-critical variations as required to replace tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate with tert-butyl 2-((1-(2-(5-chloro-6- methylpyridin-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate, 2-((1-(2-(5-chloro-6-methylpyridin-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (40 mg, 64%) was obtained as a white solid.1H NMR (400 MHz, DMSO-d6) δ 12.76 (s, 1H), 8.80 (d, J = 2.0 Hz, 1H), 8.72 (s, 1H), 8.44 ( s, 1H), 8.22 (d, J = 2.0 Hz, 1H), 7.83 - 7.78 (m, 1H), 7.69 (d, J = 1.6 Hz, 1H), 7.22 - 7.16 (m, 1H), 6.57 - 6.51 (m, 1H), 6.37 (d, J = 8.4 Hz, 1H), 5.43 - 5.33 (m, 1H), 2.64 (s, 3H), 2.34 (s, 3H), 2.25 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H). MS: m/z 463.2 (M+H+). Step 3 - Synthesis of (R)-2-((1-(2-(5-chloro-6-methylpyridin-3-yl)-3,7-dimethyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 1052) & (S)-2- ((1-(2-(5-chloro-6-methylpyridin-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid 2-((1-(2-(5-chloro-6-methylpyridin-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin- 9-yl)ethyl)amino)benzoic acid (40 mg, 86 umol) was separated by using chiral SFC (DAICEL CHIRALCEL AD (250mm*30mm,10um); Supercritical CO2 / EtOH+0.1% NH3•H2O = 40/60; 60 mL/min) to afford (R)-2-((1-(2-(5-chloro-6-methylpyridin-3-yl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 1052) (12 mg, first peak) and (S)-2-((1-(2-(5-chloro-6-methylpyridin-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (11 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. First peak: 1H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 8.80 (d, J = 2.0 Hz, 1H), 8.72 (s, 1H), 8.49 (s, 1H), 8.22 (d, J = 2.0 Hz, 1H), 7.82 - 7.78 (m, 1H), 7.69 (d, J = 1.6 Hz, 1H), 7.20 - 7.15 (m, 1H), 6.56 - 6.50 (m, 1H), 6.36 (d, J = 8.0 Hz, 1H), 5.42 - 5.33 (m, 1H), 2.64 (s, 3H), 2.34 (s, 3H), 2.26 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H). MS: m/z 463.0 (M+H+). Example 42: Preparation of (R)-2-((1-(2-(3-cyclopropylphenyl)-3,7-dimethyl-4-oxo- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 971)
Figure imgf000331_0001
Step 1 – Synthesis of tert-butyl 2-((1-(2-(3-cyclopropylphenyl)-3,7-dimethyl-4-oxo- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate Following the procedure described in Example 33, Step 1 and making non-critical variations as required to replace (3-cyanophenyl)boronic acid with (3-cyclopropylphenyl)boronic acid, tert-butyl 2-((1-(2-(3-cyclopropylphenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin- 9-yl)ethyl)amino)benzoate (135 mg, 80%) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.21 (d, J = 6.4 Hz, 1H), 7.76 (d, J = 6.4 Hz, 1H), 7.68 (s, 1H), 7.50 - 7.44 (m, 1H), 7.43 - 7.36 (m, 2H), 7.17 (d, J = 7.2 Hz, 2H), 6.56 - 6.54 (m, 1H), 6.40 (d, J = 8.8 Hz, 1H), 5.45 - 5.35 (m, 1H), 2.71 - 2.62(m, 1H), 2.34 (s, 3H), 2.22 (s, 3H), 1.62 (d, J = 6.8 Hz, 3H), 1.56 (s, 9H), 1.02 - 0.93 (m, 2H), 0.76 - 0.69 (m, 2H). MS: m/z 510.2 (M+H+). Step 2 – Synthesis of 2-((1-(2-(3-cyclopropylphenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid Following the procedure described in Example 33, Step 2 and making non-critical variations as required to replace tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate with tert-butyl 2-((1-(2-(3- cyclopropylphenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate, 2-((1-(2-(3-cyclopropylphenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (40 mg, 64%) was obtained as a white solid.1H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 8.70 (s, 1H), 8.41 (d, J = 6.4 Hz, 1H), 7.84 - 7.75 (m, 1H), 7.65 (d, J = 2.0 Hz, 1H), 7.51 - 7.45 (m, 1H), 7.43 - 7.37 (m, 2H), 7.23 - 7.15 (m, 2H), 6.57 - 6.50 (m, 1H), 6.36 (d, J = 8.4 Hz, 1H), 5.45 - 5.35 (m, 1H), 2.33 (s, 3H), 2.22 (s, 3H), 2.06 - 1.97 (m, 1H), 1.60 (d, J = 6.4 Hz, 3H), 1.02 - 0.95 (m, 2H), 0.75 - 0.70 (m, 2H). MS: m/z 454.1 (M+H+). Step 3 – Synthesis of (R)-2-((1-(2-(3-cyclopropylphenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 1075) & (S)-2-((1-(2-(3- cyclopropylphenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid 2-((1-(2-(3-cyclopropylphenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (40 mg, 88 umol) was separated by using chiral SFC (DAICEL CHIRALCEL AD (250mm*30mm,10um); Supercritical CO2 / EtOH+0.1% NH3•H2O = 20/80; 60 mL/min) to afford (R)-2-((1-(2-(3-cyclopropylphenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 1075) (11 mg, first peak) and (S)-2-((1- (2-(3-cyclopropylphenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (21 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. First peak: 1H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.44 (s, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.64 (s, 1H), 7.50 - 7.44 (m, 1H), 7.43 - 7.36 (m, 2H), 7.19 - 7.15 (m, 2H), 6.55 - 6.50 (m, 1H), 6.35 (d, J = 8.4 Hz, 1H), 5.44 - 5.35 (m, 1H), 2.32 (s, 3H), 2.21 (s, 3H), 2.06 - 1.95 (m, 1H), 1.59 (d, J = 6.4 Hz, 3H), 1.02 - 0.93 (m, 2H), 0.76 - 0.69 (m, 2H). MS: m/z 454.1 (M+H+). Example 43: Preparation of (R)-2-((1-(3,7-dimethyl-4-oxo-2-(pyridin-3-yl)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 949)
Figure imgf000333_0001
Step 1 - Synthesis of tert-butyl 2-((1-(3,7-dimethyl-4-oxo-2-(pyridin-3-yl)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate Following the procedure described in Example 33, Step 1 and making non-critical variations as required to replace (3-cyanophenyl)boronic acid with pyridin-3-ylboronic acid, tert- butyl 2-((1-(3,7-dimethyl-4-oxo-2-(pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoate (165 mg, 95%) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.95 (d, J = 2.0 Hz, 1H), 8.72 (s, 1H), 8.70 - 8.68 (m, 1H), 8.27 (d, J = 6.4 Hz, 1H), 8.18 - 8.15 (m, 1H), 7.78 - 7.70 (m, 2H), 7.59 - 7.56 (m, 1H), 7.23 - 7.16 (m, 1H), 6.55 - 6.51 (m, 1H), 6.43 (d, J = 8.4 Hz, 1H), 5.40 - 5.34 (m, 1H), 2.35 (s, 3H), 2.25 (s, 3H), 1.63 (d, J = 6.4 Hz, 3H), 1.54 (s, 9H). MS: m/z 471.1 (M+H+). Step 2 - Synthesis of tert-butyl (R)-2-((1-(3,7-dimethyl-4-oxo-2-(pyridin-3-yl)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate & tert-butyl (S)-2-((1-(3,7-dimethyl-4- oxo-2-(pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate tert-butyl 2-((1-(3,7-dimethyl-4-oxo-2-(pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoate (120 mg, 255 umol) was separated by using chiral SFC (DAICEL CHIRALCEL AD (250mm*30mm,5um); Supercritical CO2 / EtOH + 0.1% NH3•H2O = 70/30; 60 mL/min) to afford tert-butyl (R)-2-((1-(3,7-dimethyl-4-oxo-2-(pyridin-3-yl)-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (40 mg, first peak) and tert-butyl (S)-2-((1-(3,7- dimethyl-4-oxo-2-(pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (45 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. MS: m/z 471.1 (M+H+). Step 3 - Synthesis of (R)-2-((1-(3,7-dimethyl-4-oxo-2-(pyridin-3-yl)-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid Following the procedure described in Example 33, Step 2 and making non-critical variations as required to replace tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate with tert-butyl (R)-2-((1-(3,7-dimethyl-4- oxo-2-(pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate, (R)-2-((1-(3,7- dimethyl-4-oxo-2-(pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (31 mg, 76%) was obtained as a white solid.1H NMR (400 MHz, DMSO-d6) δ 12.78 (s, 1H), 8.95 (d, J = 1.6 Hz, 1H), 8.73 - 8.67 (m, 2H), 8.49 - 8.39 (m, 1H), 8.17 - 8.15 (m, 1H), 7.82 - 7.80 (m, 1H), 7.68 (d, J = 1.6 Hz, 1H), 7.62 - 7.53 (m, 1H), 7.23 - 7.12 (m, 1H), 6.56 - 6.52 (m, 1H), 6.36 (d, J = 8.4 Hz, 1H), 5.42 - 5.36 (m, 1H), 2.34 (s, 3H), 2.25 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H). MS: m/z 415.1 (M+H+). Example 44: Preparation of (R)-2-((1-(2-(6-cyclopropylpyridin-3-yl)-3,7-dimethyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 973)
Figure imgf000334_0001
Step 1 - Synthesis of tert-butyl 2-((1-(2-(6-cyclopropylpyridin-3-yl)-3,7-dimethyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate Following the procedure described in Example 33, Step 1 and making non-critical variations as required to replace (3-cyanophenyl)boronic acid with (6-cyclopropylpyridin-3- yl)boronic acid, tert-butyl 2-((1-(2-(6-cyclopropylpyridin-3-yl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (160 mg, 88%) was obtained as a white solid. MS: m/z 511.2 (M+H+). Step 2 - Synthesis of tert-butyl (R)-2-((1-(2-(6-cyclopropylpyridin-3-yl)-3,7-dimethyl- 4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate & tert-butyl (S)-2-((1-(2-(6- cyclopropylpyridin-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoate tert-butyl 2-((1-(2-(6-cyclopropylpyridin-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (130 mg, 254 umol) was separated by using chiral SFC (DAICEL CHIRALCEL IG (250mm*30mm,5um); Supercritical CO2 / MeOH + 0.1% NH3•H2O = 55/45; 80 mL/min) to afford tert-butyl (R)-2-((1-(2-(6-cyclopropylpyridin-3-yl)- 3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (50 mg, first peak) and tert-butyl (S)-2-((1-(2-(6-cyclopropylpyridin-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (50 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. MS: m/z 511.1 (M+H+). Step 3 - Synthesis of (R)-2-((1-(2-(6-cyclopropylpyridin-3-yl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid Following the procedure described in Example 33, Step 2 and making non-critical variations as required to replace tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate with tert-butyl (R)-2-((1-(2-(6- cyclopropylpyridin-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoate, (R)-2-((1-(2-(6-cyclopropylpyridin-3-yl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 1079) (16 mg, 36%) was obtained as a white solid.1H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 8.79 (d, J = 2.0 Hz, 1H), 8.70 (s, 1H), 8.42 (d, J = 5.6 Hz, 1H), 8.13 (s, 1H), 8.03 - 8.00 (m, 1H), 7.81 - 7.79 (m, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.24 - 7.15 (m, 1H), 6.56 - 6.52 (m, 1H), 6.35 (d, J = 8.4 Hz, 1H), 5.43 - 5.37 (m, 1H), 2.33 (s, 3H), 2.25 (s, 3H), 2.23 - 2.14 (m, 1H), 1.60 (d, J = 6.4 Hz, 3H), 1.06 - 0.93 (m, 4H). MS: m/z 455.1 (M+H+). Example 45: Preparation of (R)-2-((1-(2-(2-cyclopropylpyridin-4-yl)-3,7-dimethyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 953)
Figure imgf000336_0001
Step 1 - Synthesis of tert-butyl 2-((1-(2-(2-cyclopropylpyridin-4-yl)-3,7-dimethyl-4- oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate Following the procedure described in Example 33, Step 1 and making non-critical variations as required to replace (3-cyanophenyl)boronic acid with (2-cyclopropyl-4- pyridyl)boronic acid, tert-butyl 2-((1-(2-(2-cyclopropylpyridin-4-yl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (140 mg, 81%) was obtained as a yellow solid.1H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 8.59 (d, J = 5.2 Hz, 1H), 8.28 (d, J = 5.6 Hz, 1H), 7.89 (dd, J = 8.0, 1.6 Hz, 1H), 7.62 (d, J = 1.6 Hz, 1H), 7.44 (s, 1H), 7.41 - 7.35 (m, 1H), 7.17 - 7.10 (m, 1H), 6.58 - 6.54 (m, 1H), 6.27 (d, J = 8.4 Hz, 1H), 5.51 - 5.41 (m, 1H), 2.36 (s, 6H), 2.25 - 2.15 (m, 1H), 1.68 (d, J = 6.8 Hz, 3H), 1.63 (s, 9H), 1.16 - 1.10 (m, 4H). MS: m/z 511.1 (M+H+). Step 2 - Synthesis of tert-butyl (R)-2-((1-(2-(2-cyclopropylpyridin-4-yl)-3,7-dimethyl- 4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate and tert-butyl (S)-2-((1-(2-(2- cyclopropylpyridin-4-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoate tert-butyl 2-((1-(2-(2-cyclopropylpyridin-4-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoate (120 mg, 235 μmol) was separated by using chiral SFC (DAICEL CHIRALPAK IG (250mm*30mm,10μm); Supercritical CO2 / EtOH+0.1% NH3•H2O = 65/35; 80 mL/min) to afford tert-butyl (R)-2-((1-(2-(2-cyclopropylpyridin-4-yl)-3,7-dimethyl- 4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (50 mg, first peak) and tert-butyl (S)-2-((1-(2-(2-cyclopropylpyridin-4-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoate (50 mg, second peak) both as a white solid. Absolute configuration was arbitrarily assigned to each enantiomer. MS: m/z 511.2 (M+H+). Step 3 - Synthesis of (R)-2-((1-(2-(2-cyclopropylpyridin-4-yl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid Following the procedure described in Example 33, Step 2 and making non-critical variations as required to replace tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate with tert-butyl (R)-2-((1-(2-(2- cyclopropylpyridin-4-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoate, (R)-2-((1-(2-(2-cyclopropylpyridin-4-yl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 1055) (33 mg, 66%) was obtained as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 8.72 (s, 1H), 8.55 (d, J = 5.2 Hz, 1H), 8.45 (s, 1H), 7.85 - 7.78 (m, 1H), 7.69 (d, J = 1.6 Hz, 1H), 7.59 (s, 1H), 7.45 - 7.40 (m, 1H), 7.21 - 7.17 (m, 1H), 6.57 - 6.51 (m, 1H), 6.36 (d, J = 8.6 Hz, 1H), 5.55 - 5.52 (m, 1H), 2.34 (s, 3H), 2.22 - 2.21(m, 4H), 1.60 (d, J = 6.8 Hz, 3H), 1.01 - 0.96 (m, 4H). MS: m/z 455.1 (M+H+). Example 46: Preparation of (S)-2-((1-(2-(5-chloro-6-cyanopyridin-3-yl)-3,7- dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compound 978)
Figure imgf000337_0001
Step 1 – Synthesis of tert-butyl 2-((1-(2-(5-chloro-6-cyanopyridin-3-yl)-3,7-dimethyl- 4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate Following the procedure described in Example 33, Step 1 and making non-critical variations as required to replace (3-cyanophenyl)boronic acid with 3-chloro-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile, tert-butyl 2-((1-(2-(5-chloro-6-cyanopyridin- 3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (120 mg, 76%) was obtained as a white solid. MS: m/z 530.2 (M+H+). Step 2 – Synthesis of 2-((1-(2-(5-chloro-6-cyanopyridin-3-yl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid Following the procedure described in Example 33, Step 2 and making non-critical variations as required to replace tert-butyl 2-((1-(2-(3-cyanophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate with tert-butyl 2-((1-(2-(5-chloro-6- cyanopyridin-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate, 2-((1-(2-(5-chloro-6-cyanopyridin-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (40 mg, 27%) was obtained as a white solid. MS: m/z 474.1 (M+H+). Step 3 – Synthesis of (R)-2-((1-(2-(5-chloro-6-cyanopyridin-3-yl)-3,7-dimethyl-4-oxo- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid & (S)-2-((1-(2-(5-chloro-6- cyanopyridin-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (Compound 1084) 2-((1-(2-(5-chloro-6-cyanopyridin-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin- 9-yl)ethyl)amino)benzoic acid (40 mg, 84 μmol) was separated by using chiral SFC (DAICEL CHIRALPAK OD-H (250mm*30mm,5μm); Supercritical CO2 / MeOH+0.1% NH3•H2O = 50/50; 60 mL/min) to afford (R)-2-((1-(2-(5-chloro-6-cyanopyridin-3-yl)-3,7-dimethyl-4-oxo- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (15 mg, first peak) and (S)-2-((1-(2- (5-chloro-6-cyanopyridin-3-yl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (Compound 1084) (15 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. Second peak: 1H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J = 2.0 Hz, 1H), 8.74 (s, 1H), 8.61 (d, J = 2.0 Hz, 1H), 7.85 - 7.86 (m, 1H), 7.67 (s, 1H), 7.02 - 6.99 (m, 1H), 6.47 - 6.43 (m, 1H), 6.22 - 6.19 (m, 1H), 5.34 - 5.31 (m, 1H), 2.33 (s, 3H), 2.25 (s, 3H), 1.56 (d, J = 6.8 Hz, 3H). MS: m/z 474.0 (M+H+). Example 47: Preparation of 9-(1-((3-hydroxybenzo[d]isoxazol-4-yl)amino)ethyl)-3,7- dimethyl-2-(pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (Compound 1365)
Figure imgf000338_0001
Step 1 – Synthesis of 9-chloro-2-hydroxy-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4- one A solution of 3-chloro-5-methylpyridin-2-amine (5 g, 35 mmol) in acetone (60 mL) was added bis(2,4,6-trichlorophenyl) 2-methylmalonate (18.4 g, 38.6 mmol). The reaction mixture was heated to 60 °C for 2 h under N2 atmosphere. After cooling to room temperature, the reaction was filtered to give the title compound (6.7 g, 85%) as a yellow solid that required no further purification.1H NMR (400 MHz, DMSO-d6) δ 11.72 (s, 1H), 8.67 (s, 1H), 8.05 (s, 1H), 2.34 (s, 3H), 1.96 (s, 3H). Step 2 – Synthesis of 9-chloro-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl trifluoromethanesulfonate To a solution of 9-chloro-2-hydroxy-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (2.7 g, 12 mmol) in DCM (30 mL) was added pyridine (2.9 mL, 36 mmol) and Tf2O (2.38 mL, 14.4 mmol). The reaction was stirred at 0 ºC for 1 h. The reaction mixture was diluted with DCM (20 mL) and washed with 1M HCl (30 mL), and then the organic layer was washed with NaHCO3 (40 mL x 2), dried over anhydrous Na2SO4 and filtered and concentrated in vacuo to give the title compound (4.2 g, 98%) as a yellow solid that required no further purification.1H NMR (400 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.32 (s, 1H), 2.43 (s, 3H), 2.14 (s, 3H). Step 3 – Synthesis of 9-chloro-3,7-dimethyl-2-(pyridin-3-yl)-4H-pyrido[1,2- a]pyrimidin-4-one A mixture of 9-chloro-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl trifluoromethanesulfonate (6 g, 16.8 mmol), pyridin-3-ylboronic acid (2.27 mg, 18.5 mmol), Pd(PPh3)4 (972 mg, 841 μmol) and Na2CO3 (5.35 g, 50.5 mmol) in dioxane (100 mL) and H2O (10 mL). The mixture was heated to 80 °C for 10 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give the title compound (4.5 g, 86%) as brown solid.1H NMR (400MHz, DMSO-d6) δ 8.86 (s, 1H), 8.75 (s, 1H), 8.71 - 8.67 (m, 1H), 8.60 (s, 1H), 8.15 - 8.11 (m, 1H), 8.09 - 8.05 (m, 1H), 2.40 (s, 3H), 2.21 (s, 3H). MS: m/z 286.0 (M+H+). Step 4 – Synthesis of 9-acetyl-3,7-dimethyl-2-(pyridin-3-yl)-4H-pyrido[1,2- a]pyrimidin-4-one A mixture of 9-chloro-3,7-dimethyl-2-(pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (950 mg, 3.32 mmol), tributyl(1-ethoxyvinyl)stannane (3.49 g, 9.66 mmol), SPhos Pd G3 (129.7 mg, 166 umol) and CsF (1.01 g, 6.65 mmol) in toluene (10 mL) was degassed and purged with N2 for 3 times. The reaction mixture was stirred at 100 °C for 16 h under N2 atmosphere. After cooling to room temperature, HCl (6 mL, 1 M) was added. The mixture was stirred at room temperature for 0.5 h. The reaction mixture was added 15 mL 10% KF aqueous solution, stirred at room temperature for 2 h. The mixture was extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give the title compound (400 mg, 67%) as a yellow solid.1H NMR (400MHz, DMSO-d6) δ 8.94 - 8.83 (m, 2H), 8.70 - 8.67 (m, 1H), 8.11 - 8.06 (m, 1H), 7.58 - 7.54 (m, 1H), 2.73 (s, 3H), 2.44 (s, 3H), 2.23 (s, 3H). MS: m/z 294.1 (M+H+). Step 5 – Synthesis of 9-(1-aminoethyl)-3,7-dimethyl-2-(pyridin-3-yl)-4H-pyrido[1,2- a]pyrimidin-4-one To a solution of 9-acetyl-3,7-dimethyl-2-(pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (200 mg, 681 umol), NH4OAc (526 mg, 6.8 mmol) and AcOH (41 mg, 681 umol, 236 μL) in MeOH (4 mL) was added NaBH3CN (129 mg, 2.08 mmol). The reaction was heated to 60 °C for 3 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was diluted with DCM (100 mL). The mixture was washed with saturated NaHCO3 solution (20 mL x 3), brine (30 mL), dried over anhydrous Na2SO4 and filtered. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 10% DCM in MeOH) to give the title compound (40 mg, 20%) as yellow oil. 1H NMR (400MHz, DMSO-d6) δ 8.91 - 8.87 (m, 1H), 8.74 - 8.68 (m, 2H), 8.10 (d, J = 8.4 Hz, 1H), 7.91 (s, 1H), 7.61 - 7.54 (m, 1H), 4.72 - 4.65 (m, 1H), 2.43 (s, 3H), 2.22 (s, 3H), 1.36 (d, J = 6.8 Hz, 3H). MS: m/z 295.1 (M+H+). Step 6 – Synthesis of 4-((1-(3,7-dimethyl-4-oxo-2-(pyridin-3-yl)-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)-2-(2,4,6-trimethoxybenzyl)benzo[d]isoxazol-3(2H)-one A mixture of 9-(1-aminoethyl)-3,7-dimethyl-2-(pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin- 4-one (50 mg, 170 umol), 4-bromo-2-(2,4,6-trimethoxybenzyl)benzo[d] isoxazol-3(2H)-one (56 mg, 142 umol) (prepared according to the procedure in Eur. J. Med. Chem. 2018, 150, 930), Pd(OAc)2 (4 mg, 14 umol), BINAP (11 mg, 17 umol), Cs2CO3 (415 mg, 1.3 mmol) in dioxane (2 mL) was stirred at 110 °C for 5 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give the title compound (30 mg, 35%) as yellow oil. MS: m/z 608.1 (M+H+). Step 7 – Synthesis of 9-(1-((3-hydroxybenzo[d]isoxazol-4-yl)amino)ethyl)-3,7- dimethyl-2-(pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-4-one To a solution of 4-((1-(3,7-dimethyl-4-oxo-2-(pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin- 9-yl)ethyl)amino)-2-(2,4,6-trimethoxybenzyl)benzo[d]isoxazol-3(2H)-one (30 mg, 49 umol) in DCM (1.5 mL) was added TFA (0.5 mL) and triisopropylsilane (8.60 mg, 54 μmol). The mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo. The resulting residue was purified by reverse phase chromatography (acetonitrile 30% - 60% / 0.225% formic acid in water) to give the title compound (5 mg, 24%) as a white solid.1H NMR (400MHz, DMSO-d6) δ 8.94 (s, 1H), 8.75 - 8.67 (m, 2H), 8.17 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 1.6 Hz, 1H), 7.61 - 7.55 (m, 1H), 7.16 - 7.11 (m, 1H), 6.52 (d, J = 8.8 Hz, 1H), 6.38 - 6.33 (m, 1H), 6.01 (d, J = 8.4 Hz, 1H), 5.45 - 5.35 (m, 1H), 2.35 (s, 3H), 2.24 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H). MS: m/z 428.0 (M+H+). Example 48: Preparation of 2-(3-fluorophenyl)-9-(1-((2-(3-hydroxyisoxazol-5- yl)phenyl)amino)ethyl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (Compound 1367)
Figure imgf000341_0001
Step 1 - Synthesis of 9-(1-aminoethyl)-2-(3-fluorophenyl)-3,7-dimethyl-4H- pyrido[1,2-a]pyrimidin-4-one Following the procedure described in Example 47 Step 3 - Step 5 and making non-critical variations as required to replace pyridin-3-ylboronic acid with (3-fluorophenyl) boronic acid, the title compound (2 g, crude) was obtained as a yellow solid. MS: m/z 312.1 (M+H+). Step 2 - Synthesis of 9-(1-((2-bromophenyl)amino)ethyl)-2-(3-fluorophenyl)-3,7- dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one A mixture of 9-(1-aminoethyl)-2-(3-fluorophenyl)-3,7-dimethyl-4H-pyrido[1,2- a]pyrimidin-4-one (1.64 g, 5.3 mmol), 1-bromo-2-iodo-benzene (2.24 g, 7.9 mmol,), Xantphos (610 mg, 1.1 mmol), Pd2(dba)3 (482 mg, 527 μmol) and Cs2CO3 (5.15 g, 15.8 mmol) in dioxane (25 mL) was heated to 100 °C and stirred for 16 h under N2 atmosphere. After cooling to room temperature, the reaction was quenched with water (30 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-30% EtOAc in petroleum ether) to give the title compound (1.1 g, 45%) as a yellow solid.1H NMR (400MHz, DMSO-d6) δ 8.71 (s, 1H), 7.83 (d, J = 1.6 Hz, 1H), 7.59 - 7.53 (m, 3H), 7.39 - 7.34 (m, 2H), 7.05 - 7.01 (m, 1H), 6.55 - 6.46 (m, 2H), 5.79 (d, J = 8.0 Hz, 1H), 5.33 - 5.26 (m, 1H), 2.36 (s, 3H), 2.22 (s, 3H), 1.63 (d, J = 6.4 Hz, 3H). MS: m/z 466.1 (M+H+). Step 3 - Synthesis of methyl 3-(2-((1-(2-(3-fluorophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)phenyl)propiolate A mixture of 9-(1-aminoethyl)-2-(3-fluorophenyl)-3,7-dimethyl-4H-pyrido[1,2- a]pyrimidin-4-one (300 mg, 643 μmol), methyl prop-2-ynoate (216 mg, 2.6 mmol), Pd(PPh3)2Cl2 (45 mg, 64 μmol), CuI (61 mg, 322 μmol) and K2CO3 (267 mg, 1.9 mmol) in DMF (5 mL) was heated to 100 °C and stirred for 16 h under N2 atmosphere. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-25% EtOAc in petroleum ether) to give the title compound (34 mg, 11%) as yellow oil. 1H NMR (400MHz, DMSO-d6) δ 8.72 (s, 1H), 7.86 (s, 1H), 7.58 - 7.50 (m, 3H), 7.36 (d, J = 7.6 Hz, 2H), 7.19 - 7.15 (m, 1H), 6.61 - 6.43 (m, 1H), 6.44 (d, J = 8.8 Hz, 1H), 6.02 (d, J = 7.6 Hz, 1H), 5.37 - 5.33 (m, 1H), 3.75 (s, 3H), 2.36 (s, 3H), 2.22 (s, 3H), 1.62 (d, J = 6.8 Hz, 3H). MS: m/z 470.3 (M+H+). Step 4 - Synthesis of 2-(3-fluorophenyl)-9-(1-((2-(3-hydroxyisoxazol-5- yl)phenyl)amino)ethyl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one To a solution methyl 3-(2-((1-(2-(3-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)phenyl)propiolate (34 mg, 72 μmol) in EtOH (2 mL) was added hydroxylamine (10 mg, 144 μmol, 50% in water) slowly. The mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo. The resulting residue was purified by reverse phase chromatography (acetonitrile 54% - 84% / 0.225% formic acid in water) to give the title compound (12 mg, 35%) as a yellow solid.1H NMR (400MHz, DMSO- d6) δ 8.71 (s, 1H), 7.86 (s, 1H), 7.60 - 7.56 (m, 1H), 7.54 - 7.50 (m, 2H), 7.47 (d, J = 7.6 Hz, 1H), 7.35 - 7.31(m, 1H), 7.11 - 7.08 (m, 1H), 6.68 - 6.64 (m, 1H), 6.45 - 6.41 (m, 2H), 5.99 (d, J = 7.2 Hz, 1H), 5.37 - 5.34 (m, 1H), 2.34 (s, 3H), 2.23 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H). MS: m/z 471.1 (M+H+). Example 49: Preparation of (R)-2-(3-fluorophenyl)-9-(1-((2-(3-hydroxyisoxazol-5- yl)phenyl)amino)ethyl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one & (S)-2-(3- fluorophenyl)-9-(1-((2-(3-hydroxyisoxazol-5-yl)phenyl)amino)ethyl)-3,7-dimethyl-4H- pyrido[1,2-a]pyrimidin-4-one (Compound 1368 and Compound 1369)
Figure imgf000343_0001
Step 1 - Synthesis of 9-(1-aminoethyl)-2-(3-fluorophenyl)-3,7-dimethyl-4H- pyrido[1,2-a]pyrimidin-4-one 2-(3-fluorophenyl)-9-(1-((2-(3-hydroxyisoxazol-5-yl)phenyl)amino)ethyl)-3,7-dimethyl- 4H-pyrido[1,2-a]pyrimidin-4-one (15 mg, 32 μmol) was separated by using chiral SFC (DAICEL CHIRALCEL OD (250mm*30mm,10um); Supercritical CO2 / MeOH + 0.1% NH3•H2O = 60/40; 80 mL/min) to afford (R)-2-(3-fluorophenyl)-9-(1-((2-(3-hydroxyisoxazol-5- yl)phenyl)amino)ethyl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (2.3 mg, first peak) and (S)-2-(3-fluorophenyl)-9-(1-((2-(3-hydroxyisoxazol-5-yl)phenyl)amino)ethyl)-3,7-dimethyl-4H- pyrido[1,2-a]pyrimidin-4-one (2.68 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. First peak: 1H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 7.87 (s, 1H), 7.61 - 7.56 (m, 1H), 7.55 - 7.50 (m, 2H), 7.47 (d, J = 7.6 Hz, 1H), 7.35 - 7.31 (m, 1H), 7.11 - 7.08 (m, 1H), 6.68 - 6.64 (m, 1H), 6.45 - 6.41 (m, 1H), 6.45 - 6.41 (m, 2H), 5.99 (d, J = 7.2 Hz, 1H), 5.37 - 5.34 (m, 1H), 2.34 (s, 3H), 2.23 (s, 3H), 1.61 (d, J = 6.8 Hz, 3H). MS: m/z 471.2 (M+H+). Second peak: 1H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 7.86 (s, 1H), 7.58 - 7.56 (m, 1H), 7.54 - 7.50 (m, 2H), 7.46 (d, J = 7.2 Hz, 1H), 7.35 - 7.31 (m, 1H), 7.11 - 7.07(m, 1H), 6.67 - 6.63 (m, 1H), 6.44 - 6.39 (m, 2H), 5.98 (d, J = 6.8 Hz, 1H), 5.37 - 5.34 (m, 1H), 2.34 (s, 3H), 2.23 (s, 3H), 1.60 (d, J = 6.4 Hz, 3H). MS: m/z 471.2 (M+H+). Example 50: (R)-2-((1-(3,7-dimethyl-4-oxo-2-((tetrahydro-2H-pyran-4-yl)oxy)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid & (S)-2-((1-(3,7-dimethyl-4-oxo-2- ((tetrahydro-2H-pyran-4-yl)oxy)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (Compounds 1370 and Compound 1371)
Figure imgf000344_0001
Step 1 - Synthesis of tert-butyl 2-((1-(3,7-dimethyl-4-oxo-2-((tetrahydro-2H-pyran-4- yl)oxy)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate To a solution of tert-butyl 2-((1-(2-hydroxy-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a] pyrimidin-9-yl)ethyl)amino)benzoate (500 mg, 1.22 mmol), tetrahydropyran-4-ol (187 mg, 1.83 mmol), PPh3 (480 mg, 1.83 mmol) in THF (10 mL) was added DEAD (319 mg, 1.83 mmol) at 0 °C under N2 atmosphere. The mixture was stirred at room temperature for 16 h. The reaction was quenched with water (20 mL). The mixture was extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0 - 20% EtOAc in petroleum ether) to give the title compound (300 mg, 50%) as yellow oil.1H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.18 (d, J = 6.4 Hz, 1H), 7.80 - 7.71 (m, 2H), 7.25 - 7.16 (m, 1H), 6.58 - 6.52 (m, 1H), 6.38 (d, J = 8.4 Hz, 1H), 5.46 - 5.36 (m, 1H), 5.28 – 5.15 (m, 1H), 3.91 - 3.78 (m, 2H), 3.61 - 3.47 (m, 2H), 2.32 (s, 3H), 2.06 - 2.02 (m, 5H), 1.75 - 1.72 (m, 2H), 1.61 (d, J = 6.4 Hz, 3H), 1.56 (s, 9H). MS: m/z 494.3 (M+H+). Step 2 – Synthesis of 2-((1-(3,7-dimethyl-4-oxo-2-((tetrahydro-2H-pyran-4-yl)oxy)- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid To a solution of tert-butyl 2-((1-(3,7-dimethyl-4-oxo-2-((tetrahydro-2H-pyran-4-yl)oxy)- 4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoate (300 mg, 608 μmol) in DCM (6 mL) was added TFA (0.5 mL, 6.73 mmol). The reaction mixture was stirred at 40 °C for 16 h. After cooling to room temperature, the reaction mixture was concentrated and the residue was purified by reverse phase chromatography (acetonitrile 52% - 82% / 0.225% formic acid in water) to give the title compound (225 mg, 84%) as a white solid. MS: m/z 438.2 (M+H+). Step 3 – Synthesis of (R)-2-((1-(3,7-dimethyl-4-oxo-2-((tetrahydro-2H-pyran-4- yl)oxy)-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid & (S)-2-((1-(3,7-dimethyl- 4-oxo-2-((tetrahydro-2H-pyran-4-yl)oxy)-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid 2-((1-(3,7-dimethyl-4-oxo-2-((tetrahydro-2H-pyran-4-yl)oxy)-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)benzoic acid (150 mg, 304 μmol) was separated using chiral SFC (DAICEL CHIRALPAK AD 250mm*30mm,10um); Supercritical CO2 / MeOH = 60/40; 80 mL/min) to afford (R)-2-((1-(3,7-dimethyl-4-oxo-2-((tetrahydro-2H-pyran-4-yl)oxy)-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid (36 mg, first peak) and (S)-2-((1-(3,7- dimethyl-4-oxo-2-((tetrahydro-2H-pyran-4-yl)oxy)-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)benzoic acid (34 mg, second peak) as a white solid. Absolute configuration was arbitrarily assigned to each enantiomer. First peak: 1H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 8.69 (s, 1H), 8.41 (d, J = 6.0 Hz, 1H), 7.84 - 7.77 (m, 1H), 7.71 (s, 1H), 7.24 - 7.16 (m, 1H), 6.58 - 6.51 (m, 1H), 6.35 (d, J = 8.8 Hz, 1H), 5.45 - 5.35 (m, 1H), 5.27 - 5.18 (m, 1H), 3.87 - 3.83 (m, 2H), 3.61 - 3.48 (m, 2H), 2.31 (s, 3H), 2.05 - 2.03 (m, 5H), 1.79 - 1.66 (m, 2H), 1.59 (d, J = 6.4 Hz, 3H). MS: m/z 438.1 (M+H+). Second peak: 1H NMR (400 MHz, DMSO-d6) δ 12.75 (s, 1H), 8.69 (s, 1H), 8.42 (d, J = 6.0 Hz, 1H), 7.84 - 7.78 (m, 1H), 7.71 (s, 1H), 7.25 - 7.15 (m, 1H), 6.59 - 6.49 (m, 1H), 6.34 (d, J = 8.4 Hz, 1H), 5.46 - 5.36 (m, 1H), 5.28 - 5.18(m, 1H), 3.91 - 3.80 (m, 2H), 3.60 - 3.47 (m, 2H), 2.31 (s, 3H), 2.05 - 2.03 (m, 5H), 1.80 - 1.67 (m, 2H), 1.59 (d, J = 6.8 Hz, 3H). MS: m/z 438.1 (M+H+). Example 51: (R)-2-(3-fluorophenyl)-9-(1-((3-hydroxybenzo[d]isoxazol-4- yl)amino)ethyl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (Compound 1374)
Figure imgf000346_0001
Step 1 - Synthesis of 9-chloro-2-(3-fluorophenyl)-3,7-dimethyl-4H-pyrido[1,2- a]pyrimidin-4-one A mixture of 9-chloro-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl trifluoromethanesulfonate (8 g, 22.4 mmol, prepared according to Example 72, Step 2), (3- fluorophenyl)boronic acid (3.77 mg, 26.9 mmol), Pd(PPh3)4 (1.29 g, 1.1 mmol) and K2CO3 (6.30 g, 67.3 mmol) in dioxane (80 mL) and H2O (8 mL). The mixture was heated to 80 °C for 10 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was quenched with water (20 mL), diluted with EtOAc (140 mL). The mixture was stirred at room temperature for 10 minutes, then the suspension was filtered and the filter cake was dried in vacuo to give the title compound (2.2 g, 32%) was obtained as a yellow solid.1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.49 - 7.41 (m, 3H), 7.19 - 7.13 (m, 1H), 2.44 (s, 3H), 2.35 (s, 3H). MS: m/z 303.0 (M+H+). Step 2 - Synthesis of 9-acetyl-2-(3-fluorophenyl)-3,7-dimethyl-pyrido[1,2- a]pyrimidin-4-one A mixture of 9-chloro-2-(3-fluorophenyl)-3,7-dimethyl-pyrido[1,2-a]pyrimidin-4-one (3.3 g, 10.90 mmol), CsF (3.3 g, 21.80 mmol) and Sphos Pd G3 (850 mg, 1.09 mmol) in toluene (40 mL) was degassed and purged with N2 for 3 times, and then tributyl(1-ethoxyvinyl)stannane (8.3 g, 22.89 mmol) was added, the final mixture was stirred at 100 °C for 16 h under N2 atmosphere. After cooling to room temperature, HCl (8 mL, 1 M) was added. The mixture was stirred at room temperature for 0.5 h. The reaction mixture was added 80 mL 10% KF aqueous solution, stirred at room temperature for 2 h. The mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 20% EtOAc in petroleum ether) to give the title compound (2.34 g, 85%) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 8.96 (s, 1H), 7.92 (d, J = 2.0 Hz, 1H), 7.48 - 7.41 (m, 2H), 7.39 - 7.34 (m, 1H), 7.20 - 7.14 (m, 1H), 2.88 (s, 3H), 2.47 (s, 3H), 2.36 (s, 3H). MS: m/z 311.0 (M+H+). Step 3 - Synthesis of 9-(1-aminoethyl)-2-(3-fluorophenyl)-3,7-dimethyl-pyrido[1,2- a]pyrimidin-4-one To a solution of 9-acetyl-2-(3-fluorophenyl)-3,7-dimethyl-pyrido[1,2-a]pyrimidin-4-one (2.34 g, 7.5 mmol), NH4OAc (8.72 g, 113.1 mmol) and AcOH (452.83 mg, 7.5 mmol, 432 μL) in MeOH (40 mL) was added NaBH3CN (1.42 g, 22.6 mmol). The reaction was heated to 60 °C for 3 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was diluted with EtOAc (100 mL). The mixture was washed with saturated NaHCO3 solution (30 mL x 3), brine (30 mL), dried over anhydrous Na2SO4 and filtered. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 15% MeOH in EtOAc (contain 0.1% NH3·H2O)) to give the title compound (700 mg, 30%) as yellow oil.1H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 7.61 (d, J = 1.6 Hz, 1H), 7.45 - 7.41 (m, 1H), 7.37 (m, 1H), 7.34 - 7.28 (m, 1H), 7.20 - 7.06 (m, 1H), 4.83 - 4.78 (m, 1H), 2.43 (s, 3H), 2.34 (s, 3H), 1.54 (d, J = 6.8 Hz, 3H). MS: m/z 312.1 (M+H+). Step 4 - Synthesis of 4-((1-(2-(3-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)-2-(2,4,6-trimethoxybenzyl)benzo[d]isoxazol-3(2H)-one A mixture of 9-(1-aminoethyl)-2-(3-fluorophenyl)-3,7-dimethyl-pyrido[1,2-a]pyrimidin- 4-one (221 mg, 710 μmol), 4-bromo-2-(2,4,6-trimethoxybenzyl)benzo[d] isoxazol-3(2H)-one (200 mg, 507 μmol) (prepared according to the procedure in Eur. J. Med. Chem.2018, 150, 930), Pd(OAc)2 (5.7 mg, 25 μmol), BINAP (19.0 mg, 30 μmol), Cs2CO3 (1.49 g, 4.57 mmol) in dioxane (2 mL) was stirred at 110 °C for 5 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 20% EtOAc in petroleum ether) to give the title compound (130 mg, 41%) as yellow oil. MS: m/z 625.1 (M+H+). Step 5 - Synthesis of (R)-4-((1-(2-(3-fluorophenyl)-3,7-dimethyl-4-oxo-4H- pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)-2-(2,4,6-trimethoxybenzyl)benzo[d]isoxazol- 3(2H)-one & (S)-4-((1-(2-(3-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)-2-(2,4,6-trimethoxybenzyl)benzo[d]isoxazol-3(2H)-one 4-((1-(2-(3-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9- yl)ethyl)amino)-2-(2,4,6-trimethoxybenzyl)benzo[d]isoxazol-3(2H)-one (70 mg, 112 μmol) was separated by using chiral SFC (DAICEL CHIRALCEL OJ-H (250mm*30mm,10um); Supercritical CO2 / EtOH + 0.1% NH3·H2O = 50/50; 80 mL/min) to afford (R)-4-((1-(2-(3- fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)-2-(2,4,6- trimethoxybenzyl)benzo[d]isoxazol-3(2H)-one (22 mg, first peak) and (S)-4-((1-(2-(3- fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)-2-(2,4,6- trimethoxybenzyl)benzo[d]isoxazol-3(2H)-one (23 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. MS: m/z 625.1 (M+H+). Step 6 - Synthesis of (R)-2-(3-fluorophenyl)-9-(1-((3-hydroxybenzo[d]isoxazol-4- yl)amino)ethyl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one To a solution of (R)-4-((1-(2-(3-fluorophenyl)-3,7-dimethyl-4-oxo-4H-pyrido[1,2- a]pyrimidin-9-yl)ethyl)amino)-2-(2,4,6-trimethoxybenzyl)benzo[d]isoxazol-3(2H)-one (22 mg, 35 μmol) in DCM (1 mL) was added TFA (0.5 mL) and triisopropylsilane (6.3 mg, 39 μmol). The mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo. The resulting residue was purified by reverse phase chromatography (acetonitrile 53% - 83% / 0.225% formic acid in water) to give the title compound (4.7 mg, 28%) as a white solid. NMR (400MHz, DMSO-d6) δ 12.62 (s, 1H), 8.71 (s, 1H), 7.87 (d, J = 1.2 Hz, 1H), 7.61 - 7.53 (m, 3H), 7.37 - 7.32 (m, 1H), 7.22 - 7.12 (m, 1H), 6.55 (m, 1H), 6.03 (d, J = 8.0 Hz, 1H), 5.42 - 5.34 (m, 1H), 2.35 (s, 3H), 2.23 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H). MS: m/z 445.1 (M+H+). Example 52: 2-(3-fluorophenyl)-9-(1-((2-(3-hydroxyoxetan-3- yl)phenyl)amino)ethyl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (Compound 1389)
Figure imgf000348_0001
Step 1 – Synthesis of 2-(3-fluorophenyl)-9-(1-((2-iodophenyl)amino)ethyl)-3,7- dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one A mixture of 9-(1-aminoethyl)-2-(3-fluorophenyl)-3,7-dimethyl-4H-pyrido[1,2- a]pyrimidin-4-one (3.3 g, 10.6 mmol), 1,2-diiodobenzene (6.99 g, 21.2 mmol), Xantphos (613 mg, 1.1 mmol), Pd2(dba)3 (971 mg, 1.1 mmol) and Cs2CO3 (10.4 g, 31.8 mmol) in dioxane (80 mL) was heated to 100 °C and stirred for 16 h under N2 atmosphere. After cooling to room temperature, the reaction was quenched with water (50 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-10% EtOAc in petroleum ether) to give the title compound (0.8 g, 15%) as a yellow solid. MS: m/z 514.0 (M+H +). Step 2 – Synthesis of 2-(3-fluorophenyl)-9-(1-((2-(3-hydroxyoxetan-3- yl)phenyl)amino)ethyl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one To a solution of 2-(3-fluorophenyl)-9-(1-((2-iodophenyl)amino)ethyl)-3,7-dimethyl-4H- pyrido[1,2-a]pyrimidin-4-one (0.14 g, 0.27 mmol) and oxetan-3-one (37 mg, 0.51 mmol) in THF (4 mL) was added n-BuLi (0.11 ml, 0.27 mmol, 2.5 M in n-hexane ) at -78 °C under N2 atmosphere. The mixture was stirred at room temperature for 3 h under N2 atmosphere. The mixture was quenched with NH4Cl (10 mL) at 0 °C, diluted with water (20 mL), extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 68 - 98% / 0.225% formic acid in water) to give the title compound (2.6 mg, 2%) as a yellow solid.1H NMR (400MHz, DMSO-d6) δ 8.71 (s, 1H), 7.65 (s, 1H), 7.61 - 7.55 (m, 3H), 7.39 - 7.31 (m, 1H), 7.23 (d, J = 7.6 Hz, 1H), 7.00 - 6.92 (m, 1H), 6.66 - 6.57 (m, 2H), 6.27 (d, J = 8.0 Hz, 1H), 5.50 (d, J = 6.8 Hz, 1H), 5.33 - 5.25 (m, 1H), 5.04 - 4.94 (m, 2H), 4.86 - 4.77 (m, 2H), 2.34 (s, 3H), 2.24 (s, 3H), 1.53 (d, J = 6.8 Hz, 3H). MS: m/z 460.1 (M+H+). Example 53: (S)-2-(3-fluorophenyl)-9-(1-(2-(3-hydroxy-1,1-dioxidothietan-3- yl)phenoxy)ethyl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (Compound 1393)
Figure imgf000350_0001
Step 1 – Synthesis of 2-(3-fluorophenyl)-9-(1-hydroxyethyl)-3,7-dimethyl-4H- pyrido[1,2-a]pyrimidin-4-one To a solution of 9-acetyl-2-(3-fluorophenyl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4- one (1 g, 3.22 mmol) in MeOH (20 mL) was added NaBH4 (180 mg, 4.76 mmol) at 0 °C. The mixture was stirred at room temperature for 3 h under N2 atmosphere. The mixture was quenched with NH4Cl (10 mL) at 0 °C, diluted with water (20 mL), extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give the title compound (0.68 g, 68%) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 7.50 - 7.43 (m, 2H), 7.40 - 7.36 (m, 1H), 7.34 - 7.28 (m, 1H), 7.20 - 7.14 (m, 1H), 5.33 - 5.18 (m, 2H), 2.44 (s, 3H), 2.32 (s, 3H), 1.68 (d, J = 6.4 Hz, 3H). MS: m/z 313.0 (M+H+). Step 2 - Synthesis of 2-(3-fluorophenyl)-9-(1-(2-iodophenoxy)ethyl)-3,7-dimethyl-4H- pyrido[1,2-a]pyrimidin-4-one To a solution of 2-(3-fluorophenyl)-9-(1-hydroxyethyl)-3,7-dimethyl-4H-pyrido[1,2- a]pyrimidin-4-one (680 mg, 2.18 mmol) and 2-iodophenol (718 mg, 3.27 mmol) in THF (10 mL) was added PPh3 (857 mg, 3.27 mmol) and DIAD (660 mg, 3.27 mmol) at 0 °C. The mixture was stirred at room temperature for 16 h under N2 atmosphere. The solution was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give the title compound (0.6 g, 54%) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ 8.75 (s, 1H), 7.83 - 7.76 (m, 2H), 7.62 - 7.47 (m, 3H), 7.36 - 7.32 (m, 1H), 7.25 - 7.19 (m, 1H), 6.84 (d, J = 7.8 Hz, 1H), 6.73 - 6.69 (m, 1H), 6.23 - 6.17 (m, 1H), 2.40 (s, 3H), 2.22 (s, 3H), 1.70 (d, J = 6.4 Hz, 3H). MS: m/z 515.0 (M+H+). Step 3 – Synthesis of 2-(3-fluorophenyl)-9-(1-(2-(3-hydroxythietan-3- yl)phenoxy)ethyl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one To a solution of 2-(3-fluorophenyl)-9-(1-(2-iodophenoxy)ethyl)-3,7-dimethyl-4H- pyrido[1,2-a]pyrimidin-4-one (0.6 g, 1.17 mmol) and thietan-3-one (204 mg, 2.31 mmol) in THF (20 mL) was added n-BuLi (0.47 ml, 1.17 mmol, 2.5 M in n-hexane ) at -78 °C under N2 atmosphere. The mixture was stirred at room temperature for 3 h under N2 atmosphere. The mixture was quenched with NH4Cl (10 mL) at 0 °C, diluted with water (20 mL), extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give the title compound (120 mg, 22%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.62 - 7.53 (m, 3H), 7.42 - 7.31 (m, 2H), 6.99 - 6.93 (m, 1H), 6.79 (s, 1H), 6.63 - 6.58 (m, 1H), 6.25 (d, J = 8.0 Hz, 1H), 6.09 (d, J = 5.6 Hz, 1H), 5.54 - 5.25 (m, 1H), 3.74 - 3.61 (m, 4H), 2.33 (s, 3H), 2.24 (s, 3H), 1.53 (d, J = 6.4 Hz, 3H). MS: m/z 476.1 (M+H+). Step 4 – Synthesis of 2-(3-fluorophenyl)-9-(1-(2-(3-hydroxy-1,1-dioxidothietan-3- yl)phenoxy)ethyl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one To a solution of 2-(3-fluorophenyl)-9-(1-(2-(3-hydroxythietan-3-yl)phenoxy)ethyl)-3,7- dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (100 mg, 209 umol) in EtOH (4 mL) and H2O (1 mL) was added oxone (516 mg, 838 umol) at 0 °C. The mixture was stirred at room temperature for 3 h. The mixture was quenched with NaHCO3 (10 mL) at 0 °C, diluted with water (20 mL), extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 60 - 90% / 0.225% formic acid in water) to give the title compound (30 mg, 28%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 7.86 (d, J = 1.6 Hz, 1H), 7.63 - 7.43 (m, 4H), 7.38 - 7.29 (m, 1H), 7.17 -7.11 (m, 1H), 6.95 - 6.89 (m, 1H), 6.71 (d, J = 8.4 Hz, 1H), 6.53 (s, 1H), 6.24 - 6.16 (m, 1H), 5.09 - 4.94 (m, 2H), 4.26 - 4.12 (m, 2H), 2.38 (s, 3H), 2.24 (s, 3H), 1.73 (d, J = 6.4 Hz, 3H). MS: m/z 531.1 (M+Na +). Step 5 – Synthesis of (R)-2-(3-fluorophenyl)-9-(1-(2-(3-hydroxy-1,1-dioxidothietan-3- yl)phenoxy)ethyl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one & (S)-2-(3-fluorophenyl)- 9-(1-(2-(3-hydroxy-1,1-dioxidothietan-3-yl)phenoxy)ethyl)-3,7-dimethyl-4H-pyrido[1,2- a]pyrimidin-4-one 2-(3-fluorophenyl)-9-(1-(2-(3-hydroxy-1,1-dioxidothietan-3-yl)phenoxy)ethyl)-3,7- dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (30 mg, 59 umol) was separated by using chiral SFC (DAICEL CHIRALCEL AS (250 mm*30 mm,5 um); Supercritical CO2 / EtOH + 0.1% NH3•H2O = 25/75; 60 mL/min) to afford (R)-2-(3-fluorophenyl)-9-(1-(2-(3-hydroxy-1,1- dioxidothietan-3-yl)phenoxy)ethyl)-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (5.4 mg, first peak) and (S)-2-(3-fluorophenyl)-9-(1-(2-(3-hydroxy-1,1-dioxidothietan-3-yl)phenoxy)ethyl)- 3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one(15 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. First peak: 1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 7.86 (d, J = 1.6 Hz, 1H), 7.61 - 7.45 (m, 4H), 7.38 - 7.28 (m, 1H), 7.19 - 7.11 (m, 1H), 6.95 - 6.88 (m, 1H), 6.70 (d, J = 8.4 Hz, 1H), 6.55 (s, 1H), 6.24 - 6.16 (m, 1H), 5.11 - 4.91 (m, 2H), 4.23 - 4.10 (m, 2H), 2.37 (s, 3H), 2.24 (s, 3H), 1.73 (d, J = 6.4 Hz, 3H). MS: m/z 531.1 (M+Na +). Second peak: 1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 7.86 (d, J = 1.6 Hz, 1H), 7.63 - 7.44 (m, 4H), 7.39 - 7.30 (m, 1H), 7.18 -7.11 (m, 1H), 6.95 - 6.89 (m, 1H), 6.70 (d, J = 8.0 Hz, 1H), 6.54 (s, 1H), 6.24 - 6.17 (m, 1H), 5.12 - 4.90 (m, 2H), 4.25 - 4.12 (m, 2H), 2.38 (s, 3H), 2.24 (s, 3H), 1.73 (d, J = 6.4 Hz, 3H). MS: m/z 531.1 (M+Na +). Compounds of Formula (I) in Table A can be prepared analogously to Examples 1-53. Compounds of Formula (I) in Table B below were prepared analogously to Examples 1- 53. Table B
Figure imgf000352_0001
Figure imgf000353_0001
Figure imgf000354_0001
Figure imgf000355_0001
Figure imgf000356_0001
Figure imgf000357_0001
Figure imgf000358_0001
ASSAY PI3Ka cellular assay experimental procedure: SKBR3 or T47D cells are seeded in DMEM containing 10% FBS at 25k cells/well into 96-well cell culture format. Cells are incubated overnight at 37℃ in a 5% CO2 incubator and the following day cell media is aspirated, adherent cells are washed 1X with room temperature PBS prior to serum-free media application. Cells are returned to 37℃ 5% CO2 incubator and incubated a further 16hrs. Compounds are added to serum starved adherent cells with a top dose of 10,000nM and 3x multiple dose reductions for a minimum dose of 0.5nM diluted in DMSO. Cell/compound incubation continues for 1hr in a 37°C, 5% CO2 incubator prior to 10 minute PIK3CA stimulation with 20ng/ml EGF. Cells treated with 0.1% DMSO and 20ng/mL EGF are employed as negative control, cells treated with 10uM Alpelisib and 20ng/mL EGF are employed as a positive control. After 10 mins, plates are removed from incubator and cells are lysed with buffer and shaking 45 minutes.20uL of lysate is transferred to an opti-384 plate and 2.5 μl of Phospho-AKT d2 antibody with 2.5 μl of Phospho-AKT Eu Cryptate solution in the detection buffer are added to each well. 384 well plate is left overnight at room temperature before reading HTRF on an Envision plate reader. The biological activity of certain compounds using the assays described above is shown in Table A. The ranges are as follows: for T47D pAKT IC50 (nM): A denotes < 100 nM; B denotes 100 nM ≤ IC50 < 500 nM; C denotes 500 nM ≤ IC50 < 2,000 nM; and D denotes ≥ 2,000 nM. ND denotes value not determined with that assay for the specified compound; for T47D (H1047R) selectivity over SKBR3 (WT): A denotes > 20-fold; B denotes 20- fold ≥ value > 5-fold; C denotes ≤ 5-fold. ND denotes value not determined with that assay for the specified compound; and for T47D pAKT lipophilic efficiency (LiPE): A denotes > 4; B denotes 4 ≥ value > 2; C denotes ≤ 2. ND denotes value not determined with that assay for the specified compound . Table 1
Figure imgf000359_0001
Figure imgf000360_0001
Figure imgf000361_0001
Figure imgf000362_0001
Figure imgf000363_0001
Figure imgf000364_0001
Figure imgf000365_0001
Figure imgf000366_0001
Figure imgf000367_0001
Figure imgf000368_0001
Figure imgf000369_0001
Figure imgf000370_0001
Figure imgf000371_0001
Figure imgf000372_0001
Figure imgf000373_0001
Figure imgf000374_0001
Figure imgf000375_0001
Figure imgf000376_0001
Figure imgf000377_0001
Figure imgf000378_0001
Figure imgf000379_0001
Figure imgf000380_0001
Figure imgf000381_0001
Figure imgf000382_0001
Figure imgf000383_0001
Figure imgf000384_0001

Claims

WHAT IS CLAIMED IS: 1. A compound of Formula (I):
Figure imgf000385_0001
or a pharmaceutically acceptable salt thereof, wherein: R1 is hydrogen, cyano, C3-C6 cycloalkyl, C1-C6 alkyl optionally substituted with phenyl optionally substituted with halogen, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 alkoxyalkyl; R2 is phenyl optionally substituted with 1-3 independently selected R2A, 5-10 membered heteroaryl optionally substituted with 1-3 independently selected R2A, 4-10 membered heterocyclyl optionally substituted with 1-3 independently selected R2A, 4-10 membered cycloalkyl optionally substituted with 1-3 independently selected R2A, C1-C6 alkoxyalkyl optionally substituted with –C(=O)NRARC, C1-C6 alkoxy optionally substituted with – C(=O)NRARC or –O(R2B); each R2A is independently selected from: (i) halogen, (ii) cyano, (iii) hydroxyl, (iv) -NRARB, (v) -C(=O)NRARB, (vi)
Figure imgf000385_0002
(vii) -NHC(=O)RC, (viii) -C(=O)NRDRE, (ix) -C(=O)ORF, (x) -SO2RF, (xi) -NHSO2RF, (xii) -SO2NRFRG, (xiii) -NHC(=O)C1-C6 alkyl optionally substituted with NRARB, (xiv) C1-C6 haloalkyl, (xv) C1-C6 hydroxyalkyl, (xvi) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl and -NRARB, (xvii) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, -C(=O)NRARB, -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB, or C1- C6 alkyl optionally substituted with C1-C6 alkoxy or -NHC(=O)C1-C6 alkyl optionally substituted with C3-C16 cycloalkyl, (xviii) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C1-C6 alkoxy, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or – C(=O)C3-C6 cycloalkyl, (xix) C1-C6 alkoxy optionally substituted with -NRARB or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or –C(=O)C3-C6 cycloalkyl, and (xx) C3-C6 cycloalkyl optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl; R2B is phenyl optionally substituted with 1-4 independently selected R2A, 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R2A, 4-10 membered heterocyclyl optionally substituted with 1-4 independently selected R2A, 4-10 membered cycloalkyl optionally substituted with 1-4 independently selected R2A; each RA and RB is independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3- C6 cycloalkyl, C2-C6 alkenyl, –SO2(C1-C6 alkyl), and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy, or RA and RB together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C1-C6 alkyl, and –C(=O)C1-C6 alkyl; each RC is independently selected from C3-C6 cycloalkyl, -C(=O)NHRY1, or a C1-C6 alkyl optionally substituted with -NRARB or with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl; each RD and RE is independently selected from hydrogen, hydroxyl, C1-C6 alkyl, and C1- C6 alkoxy; each R3A and R3B is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl, or R3A and R3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group; R4 is hydrogen, C1-C6 alkyl, or acrylamido; R5 is hydrogen, C1-C6 alkyl, cyano, -NR5AR5B, -NR5AC(=O)R5B, or -C(=O)NR5AR5B; R5A and R5B are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 hydroxyalkyl; R6 is hydrogen, halogen, or C1-C6 alkyl; X is a bond, CH2, CH(CH3), C(CH3)2, or
Figure imgf000387_0001
Z is NR3B or O; Y is phenyl optionally substituted with 1-3 independently selected RY, naphthyl optionally substituted with 1-3 independently selected RY, or 5-10 membered heteroaryl optionally substituted with 1-3 independently selected RY; each RY is independently selected from: halogen, cyano, hydroxyl, C1-C6 haloalkyl optionally substituted with hydroxyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, - NHC(=O)RC, -C(=O)NHRY1, –CO2RA, -SO2NRFRG, -NHSO2RF, –S(=O)(=NRF)RG, –SO2(C1-C6 alkyl), -C(=O)NRARB, 4-6 membered heteroaryl, heteroaralkyl, 4-6 membered heterocyclyl optionally substituted with RY1, and C1-C6 alkyl optionally substituted with –CO2RA or 4-6 membered heteroaryl optionally substituted with RY1; RY1 is –SO2(C1-C6 alkyl), hydroxyl, or C1-C6 alkyl optionally substituted with oxo; and each RF and RG is independently selected from hydrogen, phenyl, and C1-C6 alkyl optionally substituted with oxo or –NRARB.
2. The compound of Claim 1, wherein Z is O.
3. The compound of Claim 1, wherein Z is NR3B.
4. The compound of any one of Claims 1-3, wherein R2 is phenyl optionally substituted with 1-3 independently selected R2A.
5. The compound of any one of Claims 1-3, wherein R2 is 5-10 membered heteroaryl optionally substituted with 1-3 independently selected R2A.
6. The compound of any one of Claims 1-5, wherein R2 is 4-10 membered heterocyclyl optionally substituted with 1-3 independently selected R2A.
7. The compound of any one of Claims 1-5, wherein R2 is 4-10 membered cycloalkyl optionally substituted with 1-3 independently selected R2A or –O(R2B).
8. The compound of any one of Claims 1-5, wherein R2 is C1-C6 alkoxy substituted with –C(=O)NRARC.
9. The compound of any one of Claims 1-5, wherein R2 is C1-C6 alkoxy.
10. The compound of any one of Claims 1-5, R2 is C1-C6 alkoxyalkyl optionally substituted with –C(=O)NRARC.
11. The compound of any one of Claims 1-5, R2 is C1-C6 alkoxyalkyl.
12. The compound of any one of Claims 1-11, wherein X is a bond.
13. The compound of any one of Claims 1-11, wherein X is CH2.
14. The compound of any one of Claims 1-11, wherein X is CH(CH3).
15. The compound of any one of Claims 1-11, wherein X is C(CH3)2.
16. The compound of any one of Claims 1-11, wherein X is
Figure imgf000388_0001
.
17. The compound of any one of Claims 1-16, wherein Y is phenyl optionally substituted with 1-3 independently selected RY.
18. The compound of any one of Claims 1-16, wherein Y is naphthyl optionally substituted with 1-3 independently selected RY.
19. The compound of any one of Claims 1-16, wherein Y is 5-10 membered heteroaryl optionally substituted with 1-3 independently selected RY.
20. The compound of any one of Claims 1-19, wherein RY is halogen.
21. The compound of any one of Claims 1-19, wherein RY is is hydroxyl.
22. The compound of any one of Claims 1-19, wherein RY is cyano.
23. The compound of any one of Claims 1-19, wherein RY is C1-C6 haloalkyl.
24. The compound of any one of Claims 1-19, wherein RY is C1-C6 alkoxy.
25. The compound of any one of Claims 1-19, wherein RY is C1-C6 haloalkoxy.
26. The compound of any one of Claims 1-19, wherein RY is C1-C6 hydroxyalkyl.
27. The compound of any one of Claims 1-19, wherein RY is -NHC(=O)RC.
28. The compound of any one of Claims 1-19, wherein RY is -C(=O)NHRY1.
29. The compound of any one of Claims 1-19, wherein RY is –CO2RA.
30. The compound of any one of Claims 1-19, wherein RY is -SO2NRFRG.
31. The compound of any one of Claims 1-19, wherein RY is -NHSO2RF.
32. The compound of any one of Claims 1-19, wherein RY is –S(=O)(=NRF)RG.
33. The compound of any one of Claims 1-19, wherein RY is –SO2(C1-C6 alkyl).
34. The compound of any one of Claims 1-19, wherein RY is -C(=O)NRARB.
35. The compound of any one of Claims 1-19, wherein RY is 4-6 membered heteroaryl.
36. The compound of any one of Claims 1-19, wherein RY is heteroaralkyl.
37. The compound of any one of Claims 1-19, wherein RY is 4-6 membered heterocyclyl.
38. The compound of any one of Claims 1-19, wherein RY is C1-C6 alkyl optionally substituted with –CO2RA or 5-6 membered heteroaryl optionally substituted with RY1.
39. The compound of any one of Claims 1-19, wherein RY is C1-C6 alkyl substituted with –CO2RA or 5-6 membered heteroaryl optionally substituted with RY1.
40. The compound of any one of Claims 1-19, wherein RY is C1-C6 alkyl substituted with –CO2RA or 5-6 membered heteroaryl substituted with RY1.
41. The compound of any one of Claims 1-19, wherein RY is C1-C6 alkyl substituted with –CO2RA or 5-6 membered heteroaryl.
42. The compound of any one of Claims 1-19, wherein RY is C1-C6 alkyl.
43. The compound of any one of Claims 38-40, wherein RY1 is –SO2(C1-C6 alkyl).
44. The compound of any one of Claims 38-40, wherein RY1 is C1-C6 alkyl optionally substituted with oxo.
45. The compound of any one of Claims 38-40, wherein RY1 is hydroxyl.
46. A compound selected from the group consisting of the compounds in Table A, or a pharmaceutically acceptable salt thereof.
47. A pharmaceutical composition comprising a compound of any one of Claims 1- 46, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
48. A method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Claims 1-46, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 47.
49. A method for treating cancer in a subject in need thereof, the method comprising (a) determining that the cancer is associated with a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same; and (b) administering to the subject a therapeutically effective amount of a compound of any one of Claims 1-46, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 47.
50. A method of treating a PI3Kα-associated cancer in a subject, comprising administering to a subject identified or diagnosed as having a PI3Kα-associated cancer a therapeutically effective amount of a compound of any one of Claims 1-46 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 47.
51. A method for inhibiting mutant PI3Kα activity in a mammalian cell, the method comprising contacting the mammalian cell with an effective amount of a compound of any one of Claims 1-46, or a pharmaceutically acceptable salt thereof.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN118994154A (en) * 2024-08-13 2024-11-22 山西医科大学 C3 fluoroalkylation 4H-pyrido [1,2-a ] pyrimidine-4-ketone derivative and synthesis method thereof
CN120665069A (en) * 2025-06-12 2025-09-19 军事科学院军事医学研究院军事兽医研究所 YDT compound and preparation method and application thereof

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090191177A1 (en) * 2008-01-25 2009-07-30 Ola Fjellstrom Enantiomerically Pure (-) 2-[1-(7-methyl-2-(morpholin-4-yl)-4-oxo-4H-pyrido[1,2-A]pyrimidin-9-yl)ethylamino]benzoic Acid, Its Use In Medical Therapy, And A Pharmaceutical Composition Comprising It - 026
US20110082138A1 (en) 2008-08-05 2011-04-07 Daiichi Sankyo Company, Limited Imidazopyridin-2-one derivatives
US20150210655A1 (en) 2014-01-24 2015-07-30 Astrazeneca Ab Certain (2s)-n-[(1s)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamides as dipeptidyl peptidase 1 inhibitors
WO2015140054A1 (en) 2014-03-19 2015-09-24 Boehringer Ingelheim International Gmbh Heteroaryl syk inhibitors
WO2016123629A1 (en) 2015-01-30 2016-08-04 Vanderbilt University Indazole and azaindazole substituted compounds as mglur4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
WO2017055305A1 (en) 2015-09-30 2017-04-06 Ucb Biopharma Sprl Fused pyrazole derivatives as kinase inhibitors
WO2020017125A1 (en) 2018-07-19 2020-01-23 パナソニックＩｐマネジメント株式会社 Water boat device and printing machine
WO2022164812A1 (en) * 2021-02-01 2022-08-04 Geode Therapeutics Inc. Phosphoinositide 3 kinase beta inhibitors and compositions and methods thereof
WO2023060262A1 (en) * 2021-10-07 2023-04-13 Relay Therapeutics, Inc. Pi3k-alpha inhibitors and methods of use thereof
WO2023081209A1 (en) * 2021-11-03 2023-05-11 Zeno Management, Inc. Pi3k inhibitors and methods of treating cancer

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090191177A1 (en) * 2008-01-25 2009-07-30 Ola Fjellstrom Enantiomerically Pure (-) 2-[1-(7-methyl-2-(morpholin-4-yl)-4-oxo-4H-pyrido[1,2-A]pyrimidin-9-yl)ethylamino]benzoic Acid, Its Use In Medical Therapy, And A Pharmaceutical Composition Comprising It - 026
US20110082138A1 (en) 2008-08-05 2011-04-07 Daiichi Sankyo Company, Limited Imidazopyridin-2-one derivatives
US20150210655A1 (en) 2014-01-24 2015-07-30 Astrazeneca Ab Certain (2s)-n-[(1s)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamides as dipeptidyl peptidase 1 inhibitors
WO2015140054A1 (en) 2014-03-19 2015-09-24 Boehringer Ingelheim International Gmbh Heteroaryl syk inhibitors
WO2016123629A1 (en) 2015-01-30 2016-08-04 Vanderbilt University Indazole and azaindazole substituted compounds as mglur4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
WO2017055305A1 (en) 2015-09-30 2017-04-06 Ucb Biopharma Sprl Fused pyrazole derivatives as kinase inhibitors
WO2020017125A1 (en) 2018-07-19 2020-01-23 パナソニックＩｐマネジメント株式会社 Water boat device and printing machine
WO2022164812A1 (en) * 2021-02-01 2022-08-04 Geode Therapeutics Inc. Phosphoinositide 3 kinase beta inhibitors and compositions and methods thereof
WO2023060262A1 (en) * 2021-10-07 2023-04-13 Relay Therapeutics, Inc. Pi3k-alpha inhibitors and methods of use thereof
WO2023081209A1 (en) * 2021-11-03 2023-05-11 Zeno Management, Inc. Pi3k inhibitors and methods of treating cancer

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
"UniProtKB", Database accession no. P42336
BARLAAM BERNARD ET AL: "Discovery of 9-(1-anilinoethyl)-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxamides as PI3K[beta]/[delta] inhibitors for the treatment of PTEN-deficient", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, ELSEVIER, AMSTERDAM NL, vol. 24, no. 16, 21 June 2014 (2014-06-21), pages 3928 - 3935, XP029041708, ISSN: 0960-894X, DOI: 10.1016/J.BMCL.2014.06.040 *
BAUER, T.M. ET AL., PHARMACOL. THER., vol. 146, 2015, pages 53 - 60
BIOORG. MED. CHEM. LETT., vol. 47, 2021, pages 128208
CERAMI ET AL.: "The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data", CANCER DISCOVERY, vol. 2, May 2012 (2012-05-01), pages 401, XP055599025, DOI: 10.1158/2159-8290.CD-12-0095
GAO ET AL.: "Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal", SCI. SIGNAL., vol. 6, 2013, pages 11
HANKER ET AL., CANCER DISCOVERY, vol. 9, April 2019 (2019-04-01), pages 482 - 491
MARSHALL ANDREW J ET AL: "Exploring the isoform selectivity of TGX-221 related pyrido[1,2-a]pyrimidinone-based Class IA PI 3-kinase inhibitors: Synthesis, biological evaluation and molecular modelling", BIOORGANIC & MEDICINAL CHEMISTRY, ELSEVIER, AMSTERDAM, NL, vol. 23, no. 13, 4 April 2015 (2015-04-04), pages 3796 - 3808, XP029170399, ISSN: 0968-0896, DOI: 10.1016/J.BMC.2015.03.073 *
SMITHMARCH: "Advanced Organic Chemistry", 2013
VELHO SOLIVEIRA CFERREIRA AFERREIRA ACSURIANO GSCHWARTZ S JRDUVAL ACARNEIRO FMACHADO JCHAMELIN R: "The prevalence of PIK3CA mutations in gastric and colon cancer", EUR J CANCER, vol. 41, no. 11, July 2005 (2005-07-01), pages 1649 - 54, XP025298094, DOI: 10.1016/j.ejca.2005.04.022

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN118994154A (en) * 2024-08-13 2024-11-22 山西医科大学 C3 fluoroalkylation 4H-pyrido [1,2-a ] pyrimidine-4-ketone derivative and synthesis method thereof
CN120665069A (en) * 2025-06-12 2025-09-19 军事科学院军事医学研究院军事兽医研究所 YDT compound and preparation method and application thereof

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